Publications by authors named "Minghai Tang"

78 Publications

Design, synthesis, and biological evaluation of novel covalent inhibitors targeting focal adhesion kinase.

Bioorg Med Chem Lett 2021 Dec 30;54:128433. Epub 2021 Oct 30.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China. Electronic address:

Forty-one new focal adhesion kinase (FAK) covalent inhibitors were designed and synthesized based on FAK inhibitor TAE226. Compound 11w displayed the highest inhibition of FAK with an IC value of 35 nM and exhibited potent anticancer activity against Hela, HCT116 and MDA-MB-231 cell lines with IC values of 0.41, 0.01 and 0.11 μM respectively, compared to TAE226 (2.68, 0.64 and 4.19 μM respectively). 11w also inhibited the clone formation and migration of HCT-116 cells and stimulated cell cycle arrest in the G/M phase, inducing tumor cell apoptosis. Compound 11w formed a covalent bond with the Cys427 residue of FAK in a docking model, inhibiting the autophosphorylation of FAK and downstream proteins in a dose-dependent manner. Moreover, 11w showed adequate oral bioavailability of 21.02%. A 74.20% inhibition of tumor growth in the HCT116 xenograft model was also observed. These data indicate that 11w is a promising covalent inhibitor of FAK.
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http://dx.doi.org/10.1016/j.bmcl.2021.128433DOI Listing
December 2021

Discovery of a Series of Hydroxamic Acid-Based Microtubule Destabilizing Agents with Potent Antitumor Activity.

J Med Chem 2021 10 14;64(20):15379-15401. Epub 2021 Oct 14.

State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.

Hydroxamic acid group is one of the characteristic pharmacophores of histone deacetylase (HDAC) inhibitors. But here, we discovered a series of hydroxamic acid-based microtubule destabilizing agents (MDAs), which were derived from shortening the length of the linker in HDAC6 inhibitor SKLB-23bb. Interestingly, the low nanomolar antiproliferative activity of these MDAs depended on the presence of hydroxamic acid groups, but their inhibitory effects on HDAC were lost. Among them, showed favorable metabolism stability, high bioavailability, and potent antitumor activity in multidrug-resistant cell lines and A2780/T xenograft model. More importantly, in the patient-derived xenograft models of triple-negative breast cancer and osimertinib-resistant non-small-cell lung cancer, both 20 mg/kg oral and 10 mg/kg intravenous administration of could induce more than 70% tumor inhibition without obvious toxicity. Overall, we discovered that , as a novel MDA based on hydroxamic acid, could serve as a potential MDA for further investigation.
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http://dx.doi.org/10.1021/acs.jmedchem.1c01451DOI Listing
October 2021

Elevated branched-chain α-keto acids exacerbate macrophage oxidative stress and chronic inflammatory damage in type 2 diabetes mellitus.

Free Radic Biol Med 2021 11 30;175:141-154. Epub 2021 Aug 30.

Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China. Electronic address:

Aims: Chronic inflammation is a primary reason for type 2 diabetes mellitus (T2DM) and its complications, while disordered branched-chain amino acids (BCAA) metabolism is found in T2DM, but the link between BCAA catabolic defects and inflammation in T2DM remains elusive and needs to be investigated.

Methods: The changes in BCAA catabolism, inflammation, organ damage, redox status, and mitochondrial function in db/db mice with treatments of BCAA-overload or BCAA catabolism activator were analyzed in vivo. The changes in BCAA catabolic metabolism, as well as the direct effects of BCAAs/branched-chain alpha-keto acids (BCKAs) on cytokine release and redox status were also analyzed in primary macrophages in vitro.

Results: Inactivation of branched-chain ɑ-ketoacid dehydrogenase (BCKDH) complex was found in multiple organs (liver, muscle and kidney) of db/db mice. Long-term high BCAA supplementation further increased BCKA levels, inflammation, tissue fibrosis (liver and kidney), and macrophage hyper-activation in db/db mice, while enhancing BCAA catabolism with pharmacological activator reduced these adverse effects in db/db mice. In vitro, the BCAA catabolism was unchanged in primary macrophages of db/db mice, and elevated BCKAs but not BCAAs promoted the cytokine production in primary macrophages. Moreover, BCKA stimulation was associated with increased mitochondrial oxidative stress and redox imbalance in macrophages and diabetic organs.

Conclusion: Impaired BCAA catabolism is strongly associated with chronic inflammation and tissue damage in T2DM, and this effect is at least partly due to the BCKAs-induced macrophage oxidative stress. This study highlights that targeting BCAA catabolism is a potential strategy to attenuate T2DM and its complications.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.08.240DOI Listing
November 2021

Cevipabulin-tubulin complex reveals a novel agent binding site on α-tubulin with tubulin degradation effect.

Sci Adv 2021 May 19;7(21). Epub 2021 May 19.

Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.

Microtubules, composed of αβ-tubulin heterodimers, have remained popular anticancer targets for decades. Six known binding sites on tubulin dimers have been identified thus far, with five sites on β-tubulin and only one site on α-tubulin, hinting that compounds binding to α-tubulin are less well characterized. Cevipabulin, a microtubule-active antitumor clinical candidate, is widely accepted as a microtubule-stabilizing agent by binding to the vinblastine site. Our x-ray crystallography study reveals that, in addition to binding to the vinblastine site, cevipabulin also binds to a new site on α-tubulin. We find that cevipabulin at this site pushes the αT5 loop outward, making the nonexchangeable GTP exchangeable, which reduces the stability of tubulin, leading to its destabilization and degradation. Our results confirm the existence of a new agent binding site on α-tubulin and shed light on the development of tubulin degraders as a new generation of antimicrotubule drugs targeting this novel site.
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http://dx.doi.org/10.1126/sciadv.abg4168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133757PMC
May 2021

Discovery, Optimization, and Evaluation of Quinazolinone Derivatives with Novel Linkers as Orally Efficacious Phosphoinositide-3-Kinase Delta Inhibitors for Treatment of Inflammatory Diseases.

J Med Chem 2021 07 17;64(13):8951-8970. Epub 2021 Jun 17.

Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.

Guided by molecular docking, a commonly used open-chain linker was cyclized into a five-membered pyrrolidine to lock the overall conformation of the propeller-shaped molecule. Different substituents were introduced into the pyrrolidine moiety to block oxidative metabolism. Surprisingly, it was found that a small methyl substituent could be used to alleviate the oxidative metabolism of pyrrolidine while maintaining or enhancing potency, which could be described as a "magic methyl". Further optimization around the "3rd blade" of the propeller led to identification of a series of potent and selective PI3Kδ inhibitors. Among them, compound afforded an optimum balance of PK profiles and potency. Oral administration of attenuated the arthritis severity in a dose-dependent manner in a collagen-induced arthritis model without obvious toxicity. Furthermore, demonstrated excellent pharmacokinetic properties with high bioavailability, suggesting that might be an acceptable candidate for treatment of inflammatory diseases.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00004DOI Listing
July 2021

Design, Synthesis, and Bioactivity Evaluation of Dual-Target Inhibitors of Tubulin and Src Kinase Guided by Crystal Structure.

J Med Chem 2021 06 3;64(12):8127-8141. Epub 2021 Jun 3.

State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China.

Klisyri (KX01) is a dual tubulin/Src protein inhibitor that has shown potential therapeutic effects in several tumor models. However, a phase II clinical trial in patients with bone-metastatic castration-resistant prostate cancer was halted because of lack of efficacy. We previously reported that KX01 binds to the colchicine site of β-tubulin and its morpholine group lies close to α-tubulin's surface. Thus, we hypothesized that enhancing the interaction of KX01 with α-tubulin could increase tubulin inhibition and synthesized a series of KX01 derivatives directed by docking studies. Among these derivatives, exhibited more than 10-fold antiproliferation activity in several tumor cells than KX01 and significantly improved antitumor effects. The X-ray crystal structure suggested that both bound to the colchicine site and extended into the interior of α-tubulin to form potent interactions, presenting a novel binding mode. A potential clinical candidate for cancer therapy was identified in this study.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01961DOI Listing
June 2021

Studies on the anti-psoriasis effects and its mechanism of a dual JAK2/FLT3 inhibitor flonoltinib maleate.

Biomed Pharmacother 2021 May 24;137:111373. Epub 2021 Feb 24.

State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China. Electronic address:

Psoriasis is a chronic, inflammatory autoimmune disease mediated by T cells, and characterized with abnormal proliferation and differentiation of keratinocytes, and inflammatory infiltration. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway has been identified to play essential roles in mediating various of biological processes, and is closely related to autoimmune diseases. Dendritic cells (DCs) are important antigen presenting cells and play an important regulatory role in T cells. The proliferation, differentiation and function of DCs are regulated by JAK and FMS-like tyrosine kinase 3 (FLT3) signal pathways. Flonoltinib maleate (FM), a high selectivity dual JAK2/FLT3 inhibitor with IC values of 0.8 nM and 15 nM for JAK2 and FLT3, respectively, was developed by our laboratory. Moreover, FM was a potent JAK2 inhibitor with 863-fold and 696-fold selectivity over JAK1 and JAK3, respectively. In this study, the anti-psoriasis activity of FM was evaluated both in vitro and in vivo. FM effectively inhibited the proliferation of HaCaT, the inflammatory keratinocyte induced by M5 and markedly suppressed the generation and differentiation of DCs from bone marrow (BM), and inhibited the expression of FLT3 in DCs in vitro. FM effectively inhibited the ear thickening and improved the pathological changes of the ear in interleukin (IL)-23-induced psoriasis-like acanthosis mouse model. Further in keratin 14-vascular endothelial growth factor (K14-VEGF) transgenic homozygous mice model, FM could obviously improve the psoriatic symptom and pathological changes, significantly inhibit the generations of Th1 and Th17 cells in the spleen, and the accumulations of DCs in the ears. FM could also significantly reduce the expression of various inflammatory factors both in C57BL/6 and K14-VEGF mice ears, and the serum of K14-VEGF mice. Mechanism revealed that FM effectively suppressed the phosphorylation of JAK2, STAT3 and STAT5 in inflammatory keratinocytes and the mice ears of C57BL/6 and K14-VEGF, as well as the phosphorylation of FLT3 in K14-VEGF mice ears. In conclusion, FM plays an excellent anti-psoriasis activity, including inhibiting keratinocyte proliferation and regulating inflammatory response through inhibiting JAK2 and FLT3 signaling pathway.
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http://dx.doi.org/10.1016/j.biopha.2021.111373DOI Listing
May 2021

Discovery of 3-(4-(2-((1-Indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1-pyrazol-1-yl)propanenitrile Derivatives as Selective TYK2 Inhibitors for the Treatment of Inflammatory Bowel Disease.

J Med Chem 2021 02 16;64(4):1966-1988. Epub 2021 Feb 16.

State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China.

TYK2 mediates signaling of IL-23, IL-12, and Type I IFN-driven responses that are critical in immune-mediated diseases. Herein, we report the design, synthesis, and structure-activity relationships (SARs) of 3-(4-(2-((1-indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1-pyrazol-1-yl)propanenitrile derivatives as selective TYK2 inhibitors. Among them, compound exhibited acceptable TYK2 inhibition with an IC value of 9 nM, showed satisfactory selectivity characteristics over the other three homologous JAK kinases, and performed good functional potency in the JAK/STAT signaling pathway on lymphocyte lines and human whole blood. In liver microsomal assay studies, the clearance rate and half-life of were 11.4 mL/min/g and 121.6 min, respectively. Furthermore, in a dextran sulfate sodium colitis model, reduced the production of pro-inflammatory cytokines IL-6 and TNF-α and improved the inflammation symptoms of mucosal infiltration, thickening, and edema. Taken together, was a selective TYK2 inhibitor and could be used to treat immune diseases deserving further investigation.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01468DOI Listing
February 2021

Long-Term Metabolic Correction of Phenylketonuria by AAV-Delivered Phenylalanine Amino Lyase.

Mol Ther Methods Clin Dev 2020 Dec 13;19:507-517. Epub 2020 Jan 13.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.

Phenylketonuria (PKU) is an inherited metabolic disorder caused by mutation within phenylalanine hydroxylase (PAH) gene. Loss-of-function of PAH leads to accumulation of phenylalanine in the blood/body of an untreated patient, which damages the developing brain, causing severe mental retardation. Current gene therapy strategies based on adeno-associated vector (AAV) delivery of PAH gene were effective in male animals but had little long-term effects on blood hyperphenylalaninemia in females. Here, we designed a gene therapy strategy using AAV to deliver a human codon-optimized phenylalanine amino lyase in a liver-specific manner. It was shown that PAL was active in lysing phenylalanine when it was expressed in mammalian cells. We produced a recombinant adeno-associated vector serotype 8 (AAV8) viral vector expressing the humanized PAL under the control of human antitrypsin (hAAT) promoter (AAV8-PAL). A single intravenous administration of AAV8-PAL caused long-term correction of hyperphenylalaninemia in both male and female PKU mice (strain Pah). Besides, no obvious liver injury was observed throughout the treatment process. Thus, our results established that AAV-mediated liver delivery of PAL gene is a promising strategy in the treatment of PKU.
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http://dx.doi.org/10.1016/j.omtm.2019.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733040PMC
December 2020

-(Pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine Derivatives as Selective Janus Kinase 2 Inhibitors for the Treatment of Myeloproliferative Neoplasms.

J Med Chem 2020 12 30;63(23):14921-14936. Epub 2020 Nov 30.

State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China.

In this study, we described a series of -(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine derivatives as selective JAK2 (Janus kinase 2) inhibitors. Systematic exploration of the structure-activity relationship though cyclization modification based on previously reported compound led to the discovery of the superior derivative . Compound showed excellent potency on JAK2 kinase, SET-2, and Ba/F3 cells (high expression of JAK2 mutation) with IC values of 3, 11.7, and 41 nM, respectively. Further mechanistic studies demonstrated that compound could downregulate the phosphorylation of downstream proteins of JAK2 kinase in cells. Compound also showed good selectivity in kinase scanning and potent in vivo antitumor efficacy with 82.3% tumor growth inhibition in the SET-2 xenograft model. Moreover, significantly ameliorated the disease symptoms in a Ba/F3-JAK2 allograft model, with 77.1% normalization of spleen weight, which was more potent than Ruxolitinib.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01488DOI Listing
December 2020

Ethanol extract of Liriodendron chinense (Hemsl.) Sarg barks attenuates hyperuricemic nephropathy by inhibiting renal fibrosis and inflammation in mice.

J Ethnopharmacol 2021 Jan 22;264:113278. Epub 2020 Aug 22.

Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, 610041, China. Electronic address:

Ethnopharmacological Relevance: Liriodendron chinense (Hemsl.) Sarg, known as the Chinese tulip tree, has a long history of cultivation and utilization in many Asia countries, especially in China to use in traditional Chinese medicine for expelling "wind and dampness", a term corresponding to rheumatic fever and rheumatoid arthritis. Interestingly, the barks of Liriodendron chinense (Hemsl.) Sarg was also found in folk to treat gout. However, further experimental studies remained to confirm its uric acid-lowering effects.

Aim Of The Study: The aim of the study was to evaluate the protective effect of ethanol extract of the barks of Liriodendron chinense (Hemsl.) Sarg (EELC) in a mouse model of hyperuricemic nephropathy (HN) and the involved mechanisms.

Materials And Methods: EELC at a respective dose of 250 mg/kg/d or 500 mg/kg/d were orally administered to HN mice induced by a mixture of adenine (160 mg/kg/d)/potassium oxonate (2.4 g/kg/d) for 21 days. At the end of the treatment, serum uric acid, kidney functions (serum creatinine, blood urea nitrogen and urine microalbumin), 24-h urine uric acid excretion, as well as kidney pathological changes were investigated by biochemical assay, histopathological score, immunofluorescence and histochemistry, RT-qPCR, and western blotting analysis.

Results And Discussion: Oral administration of EELC significantly lowered serum uric acid level at 500 mg/kg (185.75 ± 15.49 μmol/L of EELC vs. 238.28 ± 20.97 μmol/L of HN model, p < 0.01) in HN mice. EELC at 500 mg/kg also remarkably reduced the levels of serum creatinine (82.92 ± 7.86 μmol/L of EELC vs. 92.08 ± 6.13 μmol/L of HN model, p < 0.0001), blood urea nitrogen (21.50 ± 1.87 mmol/L of EELC vs. 29.40 ± 3.95 mmol/L of HN model, p < 0.001) and urine microalbumin (4.25 ± 0.40 mg/L of EELC vs. 5.95 ± 0.33 mg/L of HN model, p < 0.001) to improve renal function. It also attenuated renal fibrosis, especially the high-dose of EELC. Furthermore, EELC could inhibit the activation of NF-κB, ASK1/JNK/c-Jun, JAK2/STAT3 signaling pathways and reduce the release of pro-inflammatory cytokine TNF-α in the kidneys of HN mice. Additionally, EELC remarkably increased urine uric acid excretion of HN mice, which may be achieved by the upregulation of organic anion transporter 1 (OAT1), OAT3 and ATP-binding cassette subfamily G member 2 (ABCG2) proteins.

Conclusions: EELC alleviated the progression of HN by suppressing the activation of NF-κB, ASK1/JNK/c-Jun and JAK2/STAT3 signaling pathway, reducing the infiltration of inflammatory factors and uric acid accumulation in the kidney.
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http://dx.doi.org/10.1016/j.jep.2020.113278DOI Listing
January 2021

Nanomicelle protects the immune activation effects of Paclitaxel and sensitizes tumors to anti-PD-1 Immunotherapy.

Theranostics 2020 9;10(18):8382-8399. Epub 2020 Jul 9.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China.

Paclitaxel (PTX) has shown pleiotropic immunologic effects on the tumor microenvironment, and nanomicelle has emerged as a promising strategy for PTX delivery. However, the detailed mechanisms remain to be fully elucidated. Meanwhile, immunogenic cell death (ICD) is an effective approach to activate the immune system. This study investigated the ICD effect of PTX and how nanomicelle affected the immune-activation ability of PTX. The ICD effects of PTX were identified via the expression of ICD markers and cell vaccine experiment. Tumor size and overall survival in multiple animal models with treatment were monitored to evaluate the antitumor effects. The mechanisms of PTX-induced ICD and antitumor immunity were determined by detecting gene expression related to ER stress and analyzing immune cell profile in tumor after treatment. We revealed the immune-regulation mechanism of PTX nanomicelle by inducing ICD, which can promote antigen presentation by dendritic cells (DCs) and activate antitumor immunity. Notably, nanomicelle encapsulation protected the ICD effects and immune activation, which were hampered by immune system impairment caused by chemotherapy. Compared with traditional formulations, a low dose of nanomicelle-encapsulated PTX (nano-PTX) treatment induced immune-dependent tumor control, which increased the infiltration and function of both T cells and DCs within tumors. However, this antitumor immunity was hampered by highly expressed PD-1 on tumor-infiltrating CD8 T cells and upregulated PD-L1 on both immune cells and tumor cells after nano-PTX treatment. Combination therapy with a low dose of nano-PTX and PD-1 antibodies elicited CD8 T cell-dependent antitumor immunity and remarkably improved the therapeutic efficacy. Our results provide systemic insights into the immune-regulation ability of PTX to induce ICD, which acts as an inducer of endogenous vaccines through ICD effects, and also provides an experimental basis for clinical combination therapy with nano-PTX and PD-1 antibodies.
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http://dx.doi.org/10.7150/thno.45391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381738PMC
May 2021

Design, synthesis and discovery of 2(1H)-quinolone derivatives for the treatment of pulmonary fibrosis through inhibition of TGF-β/smad dependent and independent pathway.

Eur J Med Chem 2020 Jul 6;197:112259. Epub 2020 Apr 6.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, PR China. Electronic address:

Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening and interstitial lung disease with the median survival of only 3-5 years. However, due to the unclear etiology and problems in accurate diagnosis, up to now only two drugs were approved by FDA for the treatment of IPF and their outcome responses are limited. Numerous studies have shown that TGF-β is the most important cytokine in the development of pulmonary fibrosis and plays a role through its downstream signaling molecule TGF-binding receptor Smads protein. In this paper, compounds bearing 2(1H)-quinolone scaffold were designed and their anti-fibrosis effects were evaluated. Of these compounds, 20f was identified as the most active one and could inhibit TGF-β-induced collagen deposition of NRK-49F cells and mouse fibroblasts migration with comparable activity and lower cytotoxicity than nintedanib in vitro. Further mechanism studies indicated that 20f reduced the expression of fibrogenic phenotypic protein α-SMA and collagen Ⅰ by inhibiting the TGF-β/Smad dependent pathways and ERK1/2 and p38 pathways. Moreover, compared with the nintedanib, 20f (100 mg/kg/day, p.o) more effectively alleviated collagen deposition in lung tissue and delayed the destruction of lung tissue structure both in bleomycin-induced prevention and treatment mice pulmonary fibrosis models. The immunohistochemical experiments further showed that 20f could block the expression level of phosphorylated Smad3 in the lung tissue cells, which resulted in its anti-fibrosis effects in vivo. In addition, 20f demonstrated good bioavailability (F = 41.55% vs 12%, compare with nintedanib) and an appropriate elimination half-life (T = 3.5 h), suggesting that 20f may be a potential drug candidate for the treatment of pulmonary fibrosis.
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http://dx.doi.org/10.1016/j.ejmech.2020.112259DOI Listing
July 2020

Alkaloids from Black Pepper ( L.) Exhibit Anti-Inflammatory Activity in Murine Macrophages by Inhibiting Activation of NF-κB Pathway.

J Agric Food Chem 2020 Feb 18;68(8):2406-2417. Epub 2020 Feb 18.

Laboratory of Natural Product Drugs, Cancer Center, West China Medical School, West China Hospital , Sichuan University , Chengdu 610041 , People's Republic of China.

Black pepper ( L.) has been commonly utilized in food preparation and traditional medicine in several countries. Seven new amide alkaloids, pipernigramides A-G (, , , and -), a new piperic ester, pipernigrester A (), along with 47 known compounds were isolated from the EtOH extract of . The inhibitory effects on nitric oxide (NO) of all compounds were then evaluated. Among the tested compounds, three of them (-) significantly inhibited inducible nitric oxide synthase (iNOS)-mediated NO (IC = 4.74 ± 0.18, 4.08 ± 0.19, and 3.71 ± 0.32 μM, respectively), and IL-1β, IL-6, TNF-α, and PGE release in RAW 264.7 cells stimulated by lipopolysaccharide. Moreover, - suppressed IκB degradation and further inhibited the cytosol-nucleus translocation of the p65 subunit by targeting IKK-β. In the carrageenan-induced paw edema test, - demonstrated anti-inflammatory effects as well. These results indicate that all three compounds from have the potential anti-inflammatory effects.
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http://dx.doi.org/10.1021/acs.jafc.9b07754DOI Listing
February 2020

Phloretin ameliorates hyperuricemia-induced chronic renal dysfunction through inhibiting NLRP3 inflammasome and uric acid reabsorption.

Phytomedicine 2020 Jan 16;66:153111. Epub 2019 Oct 16.

Key Laboratory of Transplant Engineering and Immunology, Regenerative Medicine Research Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address:

Background: Hyperuricemia (HUA) is an important risk factor for renal diseases and contributes to renal fibrosis. It has been proved that phloretin has antioxidant and anti-inflammatory properties and could inhibit uric acid (UA) uptake in vitro. However, whether phloretin has a renal protective role in vivo remains unknown.

Purpose: This study aims to evaluate the therapeutic effect of phloretin on HUA-induced renal injury in mice and to reveal its underlying mechanism.

Methods: Mice were induced hyperuricemic by oral gavage of adenine/potassium oxonate. The effects of phloretin on renal function, fibrosis, oxidative stress, inflammation, and UA metabolism in HUA mice were evaluated. The effect of phloretin on NLRP3 pathway was analyzed in human renal tubular cell lines (HK-2).

Results: HUA mice showed renal dysfunction with increased renal fibrosis, inflammation and mitochondrial stress. By contrast, phloretin reduced the level of serum blood urea nitrogen (BUN), urinary albumin to creatinine ratio (UACR), tubular necrosis, extracellular matrix (ECM) deposition and interstitial fibroblasts in HUA mice. The renal infiltration of inflammatory cells, cytokines such as NOD-like receptor family pyrin domain containing 3 (NLRP3) and interleukin-1β (IL-1β) release, mitochondrial reactive oxygen species (ROS) and morphological lesions in HUA mice also decreased. Furthermore, phloretin partly inhibited renal glucose transporter 9 (GLUT9) and promoted urinary UA excretion in HUA mice. In vitro, phloretin suppressed the NLPR3 pathway under LPS or UA stimulation in HK-2 cells.

Conclusions: Phloretin could effectively attenuate UA-induced renal injury via co-inhibiting NLRP3 and UA reabsorption, and thus it might be a potential therapy to hyperuricemia-related renal diseases.
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http://dx.doi.org/10.1016/j.phymed.2019.153111DOI Listing
January 2020

Synthesis and discovery of new compounds bearing coumarin scaffold for the treatment of pulmonary fibrosis.

Eur J Med Chem 2020 Jan 19;185:111790. Epub 2019 Oct 19.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China. Electronic address:

Idiopathic pulmonary fibrosis, characterized by excess accumulation of extracellular matrix, involved in many chronic diseases or injuries, threatens human health greatly. We have reported a series of compounds bearing coumarin scaffold which potently inhibited TGF-β-induced total collagen accumulation in NRK-49F cell line and migration of macrophages. Compound 9d also suppressed the TGF-β-induced protein expression of COL1A1, α-SMA, and p-Smad3 in vitro. Meanwhile, 9d at a dose of 100 mg/kg/day through oral administrations for 4 weeks effectively alleviated infiltration of inflammatory cells in lung tissue and fibrotic degree in bleomycin-induced pulmonary fibrosis model, which may related to its inhibition of TGF-β/Smad3 pathway and anti-inflammation efficacy. In addition, 9d demonstrated decent bioavailability (F = 39.88%) and suitable eliminated half-life time (T = 13.09 h), suggesting that 9d could be a potential drug candidate for the treatment of fibrotic diseases.
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http://dx.doi.org/10.1016/j.ejmech.2019.111790DOI Listing
January 2020

Discovery of Potent and Orally Effective Dual Janus Kinase 2/FLT3 Inhibitors for the Treatment of Acute Myelogenous Leukemia and Myeloproliferative Neoplasms.

J Med Chem 2019 11 8;62(22):10305-10320. Epub 2019 Nov 8.

State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics , West China Hospital of Sichuan University , Chengdu 610041 , Sichuan , China.

Herein, we describe the design, synthesis, and structure-activity relationships of a series of unique 4-(1-pyrazol-4-yl)-pyrimidin-2-amine derivatives that selectively inhibit Janus kinase 2 (JAK2) and FLT3 kinases. These screening cascades revealed that was a preferred compound, with IC values of 0.7 and 4 nM for JAK2 and FLT3, respectively. Moreover, was a potent JAK2 inhibitor with 37-fold and 56-fold selectivity over JAK1 and JAK3, respectively, and possessed an excellent selectivity profile over the other 100 representative kinases. In a series of cytokine-stimulated cell-based assays, exhibited a higher JAK2 selectivity over other JAK isoforms. The oral administration of 60 mg/kg of could significantly inhibit tumor growth, with a tumor growth inhibition rate of 93 and 85% in MV4-11 and SET-2 xenograft models, respectively. Additionally, showed an excellent bioavailability ( = 58%), a suitable half-life time ( = 4.1 h), a satisfactory metabolic stability, and a weak CYP3A4 inhibitory activity, suggesting that might be a potential drug candidate for JAK2-driven myeloproliferative neoplasms and FLT3-internal tandem duplication-driven acute myelogenous leukemia.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01348DOI Listing
November 2019

Targeting glutaminase1 and synergizing with clinical drugs achieved more promising antitumor activity on multiple myeloma.

Oncotarget 2019 Oct 15;10(57):5993-6005. Epub 2019 Oct 15.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China.

Multiple myeloma (MM) pathogenesis remains incompletely understood and biomarkers predicting treatment response still remain lacking. Here we describe the rational mechanisms of combining targeting glautaminase1 (GLS1) with other chemo-reagents for MM treatment. Gls1 is highly expressed cMYC/KRAS12V-drived plasmacytoma (PCT) cells. Down-regulation of Gls1 with miRNAi in cMYC/KRAS12V-expressing BaF3 cells prevented them from growing independence of interleukin 3 (IL3). By using our cMYC/KRAS12V-transduced adoptive plasmacytoma mouse model, we found that Gls1 is involved in PCT pathogenesis. Down-regulation of Gls1 significantly prolonged the survival of PCT recipients. Knockdown of Gls1 increased the expression of Cdkn1a and Cdkn1b and decreased the expression of some critical oncogenes for cancer cell survival, such as c-Myc, Cdk4, and NfκB, as well as some genes which are essential for MM cell survival, such as Irf4, Prdm1, Csnk1α1, and Rassf5. Combination of Gls1 inhibition with LBH589, Bortezomib, or Lenalidomide significantly impaired tumor growth in a MM xenograft mouse model. Our data strongly suggest that Gls1 plays an important role for MM pathogenesis and that combination of GLS1 inhibitor with other MM therapy agents could benefit to MM patients.
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http://dx.doi.org/10.18632/oncotarget.27243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800263PMC
October 2019

Purinostat Mesylate Is a Uniquely Potent and Selective Inhibitor of HDACs for the Treatment of -Induced B-Cell Acute Lymphoblastic Leukemia.

Clin Cancer Res 2019 12 22;25(24):7527-7539. Epub 2019 Aug 22.

State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China.

Purpose: This study was to perform preclinical evaluation of a novel class I and IIb HDAC-selective inhibitor, purinostat mesylate, for the treatment of Ph B-cell acute lymphoblastic leukemia (B-ALL).

Experimental Design: Biochemical assays were used to test enzymatic activity inhibition of purinostat mesylate. Ph leukemic cell lines and patient cells were used to evaluate purinostat mesylate activity . BL-2 secondary transplantation Ph B-ALL mouse model was used to validate its efficacy, mechanism, and pharmacokinetics properties . -induced primary B-ALL mouse model and PDX mouse model derived from relapsed Ph B-ALL patient post TKI treatment were used to determine the antitumor effect of purinostat mesylate for refractory or relapsed Ph B-ALL. Long-term toxicity and hERG blockade assays were used to safety evaluation of purinostat mesylate.

Results: Purinostat mesylate, a class I and IIb HDAC highly selective inhibitor, exhibited robust antitumor activity in hematologic cancers. Purinostat mesylate at low nanomolar concentration induced apoptosis, and downregulated BCR-ABL and c-MYC expression in Ph leukemia cell lines and primary Ph B-ALL cells from relapsed patients. Purinostat mesylate efficiently attenuated Ph B-ALL progression and significantly prolonged the survival both in BL-2 secondary transplantation model with clinical patient symptoms of Ph B-ALL, -induced primary B-ALL mouse model, and PDX model derived from patients with relapsed Ph B-ALL post TKI treatment. In addition, purinostat mesylate possesses favorable pharmacokinetics and low toxicity properties.

Conclusions: Purinostat mesylate provides a new therapeutic strategy for patients with Ph B-ALL, including those who relapse after TKI treatment.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0516DOI Listing
December 2019

Flavonoids from the stems of Drake mediate cytotoxic activity through apoptosis and autophagy in cancer cells.

J Adv Res 2019 Nov 21;20:117-127. Epub 2019 Jun 21.

Lab of Natural Product Drugs and Cancer Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People's Republic of China.

In this study, systematic separation and subsequent pharmacological activity studies were carried out to identify cytotoxic natural products from the dried stems of Drake. Five previously undescribed isoflavones, pachyvones A-E; one previously undescribed xanthone, pachythone A; and twenty-two known compounds were obtained. The structures of these compounds were assigned on the basis of 1D/2D NMR data and high-resolution electrospray ionization mass spectroscopy analysis. Preliminary activity screening with HeLa and MCF-7 cells showed that ten compounds (-, , , -, , and ) had potential cytotoxicity. Further in-depth activity studies with five cancer cell lines (HeLa, HepG2, MCF-7, Hct116, and MDA-MB-231) and one normal cell line (HUVEC) revealed that these ten compounds showed specific cytotoxicity in cancer cells, with IC values ranging from 5 to 40 μM, while they had no effect on normal cell lines. To investigate whether the cytotoxicity of these ten compounds was associated with autophagy, their autophagic effects were evaluated in GFP-LC3-HeLa cells. The results demonstrated that compound (durmillone) significantly induced autophagy in a concentration-dependent manner and had the best activity as an autophagy inducer among all of the compounds. Therefore, compound was selected for further study. The PI/Annexin V double staining assay and Western blotting results revealed that compound also induced obvious apoptosis in HeLa and MCF-7 cells, which suggests that it mediates cytotoxic activity through activation of both apoptosis and autophagy. Taken together, this study identified ten natural cytotoxic products from the dried stems of Drake, of which compound induced apoptosis and autophagy and could be an anticancer drug candidate.
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http://dx.doi.org/10.1016/j.jare.2019.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626068PMC
November 2019

Hydrophobic recognition allows the glycosyltransferase UGT76G1 to catalyze its substrate in two orientations.

Nat Commun 2019 07 19;10(1):3214. Epub 2019 Jul 19.

Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 610064, Chengdu, China.

Diets high in sugar are recognized as a serious health problem, and there is a drive to reduce their consumption. Steviol glycosides are natural zero-calorie sweeteners, but the most desirable ones are biosynthesized with low yields. UGT76G1 catalyzes the β (1-3) addition of glucose to steviol glycosides, which gives them the preferred taste. UGT76G1 is able to transfer glucose to multiple steviol substrates yet remains highly specific in the glycosidic linkage it creates. Here, we report multiple complex structures of the enzyme combined with biochemical data, which reveal that the enzyme utilizes hydrophobic interactions for substrate recognition. The lack of a strict three-dimensional recognition arrangement, typical of hydrogen bonds, permits two different orientations for β (1-3) sugar addition. The use of hydrophobic recognition is unusual in a regio- and stereo-specific catalysis. Harnessing such non-specific hydrophobic interactions could have wide applications in the synthesis of complex glycoconjugates.
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http://dx.doi.org/10.1038/s41467-019-11154-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642264PMC
July 2019

PEG-derivatized birinapant as a nanomicellar carrier of paclitaxel delivery for cancer therapy.

Colloids Surf B Biointerfaces 2019 Oct 13;182:110356. Epub 2019 Jul 13.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China. Electronic address:

A novel triblock amphiphilic copolymer (PAL-PEG-Birinapant) was designed and synthesized as a dual-functional micellar carrier utilizing birinapant (an inhibitor of inhibitor-of-apoptosis proteins) as a pH-sensitive segment and inhibitor-of-apoptosis proteins-targeting ligand. The mixed micelles comprised of PAL-PEG-Birinapant (PPB) and mPEG2k-PDLLA2k (MPP), named as PPB/MPP (2/1,w/w) micelles were developed for enhanced solubility and antitumor potency of hydrophobic drugs as paclitaxel (PTX). In vitro cell viability and cytotoxicity studies revealed that the PTX-loaded PPB/MPP micelles were more potent than the commercial PTX formulation (Taxol), as well as the in vitro cell apoptosis study. Clear differences in the intracellular uptake of free coumarin-6 (C6) solution and C6-loaded PPB/MPP micelles were observed and indicated that the PPB/MPP micelles could efficiently deliver chemical compound into tumor cells. PPB copolymer and PTX-loaded PPB/MPP micelles demonstrated an excellent safety profile with a maximum tolerated dose (MTD) of above 1.2 g copolymer/kg and above 100 mg PTX/kg in mice respectively in contrast to 20˜24 mg/kg of Taxol®. The near infrared (NIR) fluorescence imaging showed that PPB/MPP micelles persisted for a relatively long time in the circulation and accumulated preferentially in tumor tissue. Moreover, PTX loaded PPB/MPP micelles significantly inhibited the tumor growth both in MDA-MB-231 and Ramos cancer xenograft mice models without obvious toxicity. Collectively, our study presents a new dual-functional micelles that improve the therapeutic efficacy of PTX in vitro and in vivo.
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http://dx.doi.org/10.1016/j.colsurfb.2019.110356DOI Listing
October 2019

Microbial and metabolomic remodeling by a formula of Sichuan dark tea improves hyperlipidemia in apoE-deficient mice.

PLoS One 2019 3;14(7):e0219010. Epub 2019 Jul 3.

Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China.

Medicine-food homology is a long-standing concept in traditional Chinese medicine. YiNianKangBao (YNKB) tea is a medicine-food formulation based on Sichuan dark tea (Ya'an Tibetan tea), which is traditionally used for its lipid-lowering properties. In this study, we evaluated the effects of YNKB on dyslipidemia and investigated the mechanism underlying its correlation with gut microbiota and serum metabolite regulation. Wild-type mice were fed a normal diet as a control. Male ApoE-/- mice were randomly divided into three high-fat diet (HFD) groups, a model group, and two treated groups (100, 400 mg/kg/d for low, high-dose), and fed by gavage for 12 weeks. Serum lipid levels, composition of gut microbiota, and serum metabolites were then analyzed before treatment with YNKB. We extracted the ingredients of YNKB in boiled water for one hour. YNKB supplementation at a high dose of 400 mg/kg/day reduced bodyweight gains (relative epididymal fat pad and liver weight), and markedly attenuated serum lipid profiles and atherosclerosis index, with no significant differences present between the low-dose treatment and HFD groups. Gut microbiota and serum metabolic analysis indicated that significant differences were observed between normal, HFD, and YNKB treatment groups. These differences in gut microbiota exhibited strong correlations with dyslipidemia-related indexes and serum metabolite levels. Oral administration of high-dose YNKB also showed significant lipid-lowering activity against hyperlipidemia in apoE-deficient mice, which might be associated with composition alterations of the gut microbiota and changes in serum metabolite abundances. These findings highlight that YNKB as a medicine-food formulation derived from Sichuan dark tea could prevent dyslipidemia and improve the understanding of its mechanisms and the pharmacological rationale for preventive use.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219010PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608967PMC
March 2020

Anti-Tumor Study of H6, a 4-Substituted Coumarins Derivative, Loaded Biodegradable Self-Assembly Nano-Micelles and .

J Biomed Nanotechnol 2019 Jul;15(7):1515-1531

In our previous study, we identified a class of 4-substituted coumarins as a powerful microtubule inhibitors binding to the colchicine site of -tubulin. H6 showed potent anti-proliferative ability with IC values from 7 to 47 nM, and remarkable ability to reduce tumor growth in several xenograft models including taxol resistant tumor models. However, the extremely hydrophobicity limited its clinical application. In this study, to improve the anticancer activity and reduce the toxicity of H6, we successfully prepared MPEG-PCL with different proportions and H6-loaded polymeric micelles (H6/MPEG2kPCL2k micelles) by a simple thin-film hydration method. The prepared H6/MPEG-PCL micelles had a drug loading of 3.79 ± 0.001%, an encapsulation efficiency of 98.00 ± 0.41%, a mean particle size of 30.45 ± 0.18nm and a polydispersity index (PDI) of 0.096 ± 0.009. Computer simulation results revealed a good compatibility of H6 and MPEG-PCL copolymer. In release study and pharmacokinetic study showed H6 micelles can release H6 over an extended period. Furthermore, H6 micelles possessed comparative effect as free H6 in inhibiting cell growth, preventing cell migration, and inducing apoptosis. Mechanism study identified that H6 is a novel reversible microtubule inhibitor. In studies, H6 micelles exhibited tumor growth inhibition on two pulmonary metastatic tumor models (B16/F10 and 4T1). Importantly, H6 micelles significantly improved the solubility, reduced the toxicity, extended the half-life of drugs, and augmented the therapeutic window. All these results imply that H6 micelles have great potential for suppression of tumor metastasis.
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http://dx.doi.org/10.1166/jbn.2019.2797DOI Listing
July 2019

Discovery of 1,2,4-oxadiazole-Containing hydroxamic acid derivatives as histone deacetylase inhibitors potential application in cancer therapy.

Eur J Med Chem 2019 Sep 3;178:116-130. Epub 2019 Jun 3.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. Electronic address:

In this study, a series of novel HDAC inhibitors, using 1,2,4-oxadiazole-containing as the cap group, were synthesized and evaluated in vitro. Compound 14b, N-hydroxy-2-(methyl((3-(1-(4-methylbenzyl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methyl)amino)pyrimidine-5-carboxamide, displayed the most potent histone deacetylase (HDAC) inhibition, especially against HDAC1, 2, and 3 with IC values of 1.8, 3.6 and 3.0 nM, respectively. In vitro antiproliferative studies confirmed that 14b was more potent than SAHA, with IC values against 12 types of cancer cell lines ranging from 9.8 to 44.9 nM. The results of Western blot assays showed that compound 14b can significantly up-regulate the acetylation of the biomarker his-H and molecular docking analyses revealed the mode of action of compound 14b against HDAC1. The results of flow-cytometry analysis suggested that compound 14b induces cell cycle arrest at the G1 phase and has apoptotic effects. Further investigation of the activity of 14b on the primary cells of three patients, showed IC values of 21.3, 61.1, and 77.4 nM. More importantly, an oral bioavailability of up to 53.52% was observed for 14b. An in vivo pharmacodynamic evaluation demonstrated that compound 14b can significantly inhibit tumor growth in a Daudi Burkitt's lymphoma xenograft model, with tumor inhibition rates of 53.8 and 46.1% observed at 20 and 10 mg/kg when administered p.o. and i.v., respectively. These results indicate that compound 14b may be a suitable lead for further evaluation and development as an HDAC inhibitor and a potent anticancer agent.
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http://dx.doi.org/10.1016/j.ejmech.2019.05.089DOI Listing
September 2019

Identification of Pyrrolo[2,3- d]pyrimidine-Based Derivatives as Potent and Orally Effective Fms-like Tyrosine Receptor Kinase 3 (FLT3) Inhibitors for Treating Acute Myelogenous Leukemia.

J Med Chem 2019 04 15;62(8):4158-4173. Epub 2019 Apr 15.

A series of pyrrolo[2,3- d]pyrimidine derivatives were prepared and optimized for cytotoxic activities against FLT3-ITD mutant cancer cells. Among them, compound 9u possessed nanomolar FLT3 inhibitory activities and subnanomolar inhibitory activities against MV4-11 and Molm-13 cells. It also showed excellent inhibitory activities in FLT3-ITD-D835V and FLT3-ITD-F691L cells which were resistant to quizartinib. Furthermore, 9u exhibited over 40-fold selectivity toward FLT3 relative to c-Kit kinase, which might reduce myelosuppression toxicity. Cellular assays demonstrated that 9u inhibited phosphorylated FLT3 and downstream signaling factors and also induced cell cycle arrest in the G/G stage and apoptosis in MV4-11 and Molm-13 cells. Oral administration of 9u at 10 mg/kg could achieve rapid tumor extinction in the MV4-11 xenograft model and significantly inhibit the tumor growth in the MOLM-13 xenograft model with a tumor growth inhibitory rate of 96% without obvious toxicity. Additionally, 9u demonstrated high bioavailability ( F = 59.5%) and suitable eliminated half-life time ( T = 2.06 h), suggesting that 9u may be a potent candidate for treating acute myelogenous leukemia.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00223DOI Listing
April 2019

Discovery of Novel Dual Histone Deacetylase and Mammalian Target of Rapamycin Target Inhibitors as a Promising Strategy for Cancer Therapy.

J Med Chem 2019 02 24;62(3):1577-1592. Epub 2019 Jan 24.

In the present study, a series of novel dual-target histone deacetylase (HDAC) and mammalian target of rapamycin (mTOR) inhibitors were designed and synthesized using pyrimidine-pyrazolyl pharmacophore to append HDAC recognition cap and hydroxamic acid as a zinc-binding motif. Among them, 12l was the optimal lead compound with potent inhibition activities against mTOR and HDAC1 with half-maximal inhibitory concentration of 1.2 and 0.19 nM, respectively. Western blot confirmed that 12l could upregulate acetylation of H3 and α-tubulin and downregulate mTOR-related downstream mediators. 12l could also stimulate cell cycle arrest in G/G phase and induce tumor cell apoptosis. 12l showed comparable antitumor activity with the combination medication in MM1S xenograft model with a tumor growth inhibitory rate of 72.5%, without causing significant loss of body weight and toxicity. All of the results indicated that 12l could be a promising dual target inhibitor for treating hematologic malignancies.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01825DOI Listing
February 2019

Discovery and synthesis of novel magnolol derivatives with potent anticancer activity in non-small cell lung cancer.

Eur J Med Chem 2018 Aug 27;156:190-205. Epub 2018 Jun 27.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China; School of Pharmacy, Chengdu University of TCM, The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicine, State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, 611137, PR China. Electronic address:

EGFR T790 M accounts for 50% to 60% of cases of non-small-cell lung carcinoma (NSCLC) resistance to the first-generation EGFR tyrosine kinase inhibitors (TKIs). Hence, identifying novel compounds with activity against TKIs resistant is of great value. In this study, twenty honokiol and magnolol derivatives were isolated from the EtOH extract of Magnolia officinalis and the antiproliferative activity was evaluated on HCC827 (19del EGFR mutation), H1975 (L858 R/T790 M EGFR mutation), and H460 (KRAS mutation) cell lines. Among the isolated compounds, piperitylmagnolol (a 3-substituted magnolol derivative) showed the best antiproliferative activity against those three cell lines with the IC values of 15.85, 15.60 and 18.60 μM, respectively, which provided a direction for the structural modification of magnolol. Further structural modification led to the synthesis of thirty-one magnolol derivatives, and compounds A13, C1, and C2 exhibited significant and broad-spectrum antiproliferative activity with the IC values ranging from 4.81 to 13.54 μM, which were approximately 4- and 8-fold more potent than those of honokiol and magnolol, respectively. Moreover, their aqueous solubility was remarkably improved with 12-, 400- and 10 fold greater than those of honokiol and magnolol. Anti-tumor mechanism research revealed that these three compounds were able to induce cell cycle arrest at G0/G1 phase, cause efficient apoptosis in H1975 cells, and also prevent the migration of HUVECs in a dose-dependent manner through Cdk2, Cdk4, Cyclin E, and Cyclin D1 inhibition as well as up-regulation of cleaved-PARP and cleaved-caspase 3 levels. In in vivo antitumor activity, C2 (10, 30 and 100 mg/kg, po) dose-dependently inhibited the tumor growth in H1975 xenograft model with the tumor inhibition rate of 46.3%, 59.3% and 61.2% respectively, suggesting that C2 is a potential oral anticancer agent deserving further investigation.
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http://dx.doi.org/10.1016/j.ejmech.2018.06.048DOI Listing
August 2018
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