Publications by authors named "Qidong You"

173 Publications

Discovery of a covalent inhibitor of heat shock protein 90 with antitumor activity that blocks the co-chaperone binding via C-terminal modification.

Cell Chem Biol 2021 Apr 26. Epub 2021 Apr 26.

State Key Laboratory of Natural Medicines, and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Heat shock protein (Hsp90), a critical molecular chaperone that regulates the maturation of a large number of oncogenic client proteins, plays an essential role in the growth of neoplastic cells. Herein, DDO-6600 is identified to covalent modification of Cys598 on Hsp90 from in silico study and is verified by a series of biological assays. We demonstrated that DDO-6600 covalently bound to Cys598 on the Hsp90 C terminus and exhibited antiproliferative activities against multiple tumor cells without inhibiting ATPase activity. Further studies showed that DDO-6600 disrupted the interaction between Hsp90 and Cdc37, which induced the degradation of kinase client proteins in multiple tumor cell lines, promoted apoptosis, and inhibited cell motility. Our findings offer mechanic insights into the covalent modification of Hsp90 and provide an alternative strategy for the development of Hsp90 covalent regulators or chemical probes to explore the therapeutical potential of Hsp90.
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http://dx.doi.org/10.1016/j.chembiol.2021.03.016DOI Listing
April 2021

Targeting the HSP90-CDC37-kinase chaperone cycle: A promising therapeutic strategy for cancer.

Med Res Rev 2021 Apr 12. Epub 2021 Apr 12.

State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.

Heat shock protein 90 (HSP90) is an indispensable molecular chaperone that facilitates the maturation of numerous oncoproteins in cancer cells, including protein kinases, ribonucleoproteins, steroid hormone receptors, and transcription factors. Although over 30 HSP90 inhibitors have steadily entered clinical trials, further clinical advancement has been restricted by their limited efficacy, inevitable heat shock response, and multiple side-effects, likely induced via an ATP inhibition mechanism. Since both ATP and various co-chaperones play essential roles in the HSP90 chaperone cycle to achieve integrated function, optimal therapeutics require an understanding of the dynamic interactions among HSP90, ATP, and cochaperones. To date, continuous research has promoted the exploration of the cochaperone cell division cycle 37 (CDC37) as a kinase-specific recognizer and has shown that the HSP90-CDC37-kinase complex is particularly relevant in cancers. Indeed, disrupting the HSP90-CDC37-kinase complex, rather than totally blocking the ATP function of HSP90, is emerging as an alternative way to avoid the limitations of current inhibitors. In this review, we first briefly introduce the HSP90-CDC37-kinase cycle and present the currently available approaches for inhibitor development targeting this cycle and provide insights into selective regulation of the kinase clients of HSP90 by more directional ways.
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http://dx.doi.org/10.1002/med.21807DOI Listing
April 2021

Hydrogen Peroxide Inducible JAK3 Covalent Inhibitor: Prodrug for the Treatment of RA with Enhanced Safety Profile.

ACS Med Chem Lett 2020 Nov 5;11(11):2182-2189. Epub 2020 Oct 5.

State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.

Selective inhibition of Janus kinases (JAKs) is an arising strategy in drug discovery. Covalent inhibitors targeting a unique cysteine in JAK3 exhibit ultraselectivity among JAK family members. However, safety and tissue specific concerns still remain. A prodrug of a known JAK3 covalent inhibitor sensitive to HO was designed and synthesized and its therapeutic effect was evaluated in the CIA (collagen-induced arthritis) mice model of RA (rheumatoid arthritis). The prodrug strategy relied on the introduction of a hydrogen peroxide-sensitive borate trigger group to avoid random covalent binding to thiol functionalities in biomacromolecules. The results show that the prodrug can be activated and released under pathophysiological concentration of HO. In addition, the prodrug demonstrated stability to the physiological environment. In comparison to the parent compound, the prodrug showed a similar therapeutic effect in the CIA model but notably exhibited lower toxicity and a larger therapeutic window.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667863PMC
November 2020

Modulation of protein fate decision by small molecules: targeting molecular chaperone machinery.

Acta Pharm Sin B 2020 Oct 7;10(10):1904-1925. Epub 2020 Feb 7.

State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.

Modulation of protein fate decision and protein homeostasis plays a significant role in altering the protein level, which acts as an orientation to develop drugs with new mechanisms. The molecular chaperones exert significant biological functions on modulation of protein fate decision and protein homeostasis under constantly changing environmental conditions through extensive protein-protein interactions (PPIs) with their client proteins. With the help of molecular chaperone machinery, the processes of protein folding, trafficking, quality control and degradation of client proteins could be arranged properly. The core members of molecular chaperones, including heat shock proteins (HSPs) family and their co-chaperones, are emerging as potential drug targets since they are involved in numerous disease conditions. Development of small molecule modulators targeting not only chaperones themselves but also the PPIs among chaperones, co-chaperones and clients is attracting more and more attention. These modulators are widely used as chemical tools to study chaperone networks as well as potential drug candidates for a broader set of diseases. Here, we reviewed the key checkpoints of molecular chaperone machinery HSPs as well as their co-chaperones to discuss the small molecules targeting on them for modulation of protein fate decision.
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http://dx.doi.org/10.1016/j.apsb.2020.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606112PMC
October 2020

Design, synthesis and bioevaluation of inhibitors targeting HSP90-CDC37 protein-protein interaction based on a hydrophobic core.

Eur J Med Chem 2021 Jan 22;210:112959. Epub 2020 Oct 22.

State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address:

HSP90-CDC37 protein-protein interaction (PPI) works as a kinase specific-molecular chaperone system to regulate the maturation of kinases. Currently, selectively disrupting HSP90-CDC37 PPI, rather than the direct inhibition of the ATPase function of HSP90, is emerging as a promising strategy for cancer therapy by specifically blocking the maturation of kinases. However, due to the limited understanding of HSP90-CDC37 binding interface, design of small molecule inhibitors targeting HSP90-CDC37 PPI is challenging. In this work, based on the binding mode of compound 11 (previously reported by our group), we discovered a hydrophobic pocket centered on Phe213, which was previously unknown, contributing to the binding affinity of HSP90-CDC37 PPI inhibitors. A series of hydrophobic substituted inhibitors were utilized to confirm the importance of Phe213 hydrophobic core. Finally, we obtained an optimum compound DDO-5994 (exhibited an ideal binding pattern on hydrophobic core) with improved binding affinity (K = 5.52 μM) and antiproliferative activity (IC = 6.34 μM). Both in vitro and in vivo assays confirmed DDO-5994 as a promising inhibitor to exhibit ideal antitumor efficacy through blocking HSP90-CDC37 PPI.
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http://dx.doi.org/10.1016/j.ejmech.2020.112959DOI Listing
January 2021

Discovery of Clinical Candidate (5-(3-(4-Chlorophenoxy)prop-1-yn-1-yl)-3-hydroxypicolinoyl)glycine, an Orally Bioavailable Prolyl Hydroxylase Inhibitor for the Treatment of Anemia.

J Med Chem 2020 09 5;63(17):10045-10060. Epub 2020 Aug 5.

State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.

The design and discovery of a new series of (5-alkynyl-3-hydroxypicolinoyl)glycine inhibitors of prolyl hydroxylase (PHD) are described. These compounds showed potent in vitro inhibitory activity toward PHD2 in a fluorescence polarization-based assay. Remarkably, oral administration of , with an IC of 64.2 nM toward PHD2, was found to stabilize HIF-α, elevate erythropoietin (EPO), and alleviate anemia in a cisplatin-induced anemia mouse model with an oral dose of 25 mg/kg. Rat and dog studies showed that has good pharmacokinetic properties, with oral bioavailabilities of 55.7 and 54.0%, respectively, and shows excellent safety profiles even at a high dose of 200 mg/kg in these animals. Based on these results, is currently being evaluated in a phase I clinical trial for anemia.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01161DOI Listing
September 2020

A hydrogen peroxide responsive prodrug of Keap1-Nrf2 inhibitor for improving oral absorption and selective activation in inflammatory conditions.

Redox Biol 2020 07 11;34:101565. Epub 2020 May 11.

State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address:

Transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) and its negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (Keap1), control the redox and metabolic homeostasis and oxidative stress. Inhibitors of Keap1-Nrf2 interaction are promising in oxidative stress related inflammatory diseases but now hit hurdles. By utilizing thiazolidinone moiety to shield the key carboxyl pharmacophore in Keap1-Nrf2 inhibitor, a hydrogen peroxide (HO)-responsive prodrug pro2 was developed. The prodrug modification improved the physicochemical properties and cell membrane permeability of the parent drug. Pro2 was stable and stayed inactive under various physiological conditions, while became active by stimulation of HO or inflammation derived reactive oxygen species. Moreover, pro2 exhibited proper pharmacokinetic profile suitable for oral administration and enhanced anti-inflammatory efficiency in vivo. Thus, this novel prodrug approach may not only provide an important advance in the therapy of chronic inflammatory diseases with high level of HO, but also offer a fresh solution to improve the drug-like and selectivity issues of Keap1-Nrf2 inhibitors.
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http://dx.doi.org/10.1016/j.redox.2020.101565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231841PMC
July 2020

Recent developments of small molecules targeting RNA mA modulators.

Eur J Med Chem 2020 Jun 15;196:112325. Epub 2020 Apr 15.

Jiangsu Key Laboratory of Drug Design and Optimization, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address:

N-methyladenosine (mA) is the most abundant internal post-transcriptional modification in eukaryotic mRNA. The development of emerging technologies such as mA-seq, has helped reveal the fundamental role of mA-RNA in regulation of the mammalian transcriptome. With the identification and advances in the understanding of mA modulators, the relationship between mA and human diseases is gradually being revealed. This review summarizes recent progress in the understanding of the role of mA modulators in human disease and their structural characteristics. We highlight the potential of small-molecule regulators targeting mA associated proteins as tool molecules and disease treatment options from the medicinal chemistry perspective.
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http://dx.doi.org/10.1016/j.ejmech.2020.112325DOI Listing
June 2020

Combined Omics Approach Identifies Gambogic Acid and Related Xanthones as Covalent Inhibitors of the Serine Palmitoyltransferase Complex.

Cell Chem Biol 2020 05 23;27(5):586-597.e12. Epub 2020 Apr 23.

Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA. Electronic address:

In this study, we identify the natural product gambogic acid as well as structurally related synthetic xanthones as first-in-class covalent inhibitors of the de novo sphingolipid biosynthesis. We apply chemoproteomics to determine that gambogic acid binds to the regulatory small subunit B of the serine palmitoyltransferase complex (SPTSSB). We then test structurally related synthetic xanthones to identify 18 as an equally potent but more selective binder of SPTSSB and show that 18 reduces sphingolipid levels in situ and in vivo. Finally, using various biological methods, we demonstrate that 18 induces cellular responses characteristic for diminished sphingosine-1-phosphate (S1P) signaling. This study demonstrates that SPTSSB may become a viable therapeutic target in various diseases with pathological S1P signaling. Furthermore, we believe that our compound will become a valuable tool for studying the sphingolipid metabolism and serve as a blueprint for the development of a new generation of sphingolipid biosynthesis inhibitors.
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http://dx.doi.org/10.1016/j.chembiol.2020.03.008DOI Listing
May 2020

p62 as a therapeutic target for tumor.

Eur J Med Chem 2020 May 17;193:112231. Epub 2020 Mar 17.

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address:

p62/SQSTM1 (hereafter as p62) is a stress-inducible cellular protein, which interacts with various signaling proteins to regulate a variety of cellular functions. Growing lines of evidence supported a critical role of p62 in tumorigenesis, and p62 may become a therapeutic target for tumor. In this review, we summarize biological functions of structural domains of p62, reported bioactive molecules targeting p62, and the relationship between p62 and tumorigenesis.
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http://dx.doi.org/10.1016/j.ejmech.2020.112231DOI Listing
May 2020

Corrigendum to "Wogonin inhibits LPS-induced vascular permeability via suppressing MLCK/MLC pathway" [Vascular pharmacology 72 (2015) 43-52].

Vascul Pharmacol 2020 May - Jun;128-129:106612. Epub 2020 Mar 11.

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.

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http://dx.doi.org/10.1016/j.vph.2019.106612DOI Listing
March 2020

Correction: Wogonin induces cell cycle arrest and erythroid differentiation in imatinib-resistant K562 cells and primary CML cells.

Oncotarget 2020 Jan 21;11(3):300-301. Epub 2020 Jan 21.

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, People's Republic of China.

[This corrects the article DOI: 10.18632/oncotarget.2340.].
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http://dx.doi.org/10.18632/oncotarget.27373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980629PMC
January 2020

Discovery and Optimization of Small Molecules Targeting the Protein-Protein Interaction of Heat Shock Protein 90 (Hsp90) and Cell Division Cycle 37 as Orally Active Inhibitors for the Treatment of Colorectal Cancer.

J Med Chem 2020 02 24;63(3):1281-1297. Epub 2020 Jan 24.

State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization , China Pharmaceutical University , Nanjing 210009 , China.

Cell division cycle 37 (Cdc37) is known to work as a kinase-specific cochaperone, which selectively regulates the maturation of kinases through protein-protein interaction (PPI) with Hsp90. Directly disrupting the Hsp90-Cdc37 PPI is emerging as an alternative strategy to develop anticancer agents through a specific inhibition manner of kinase clients of Hsp90. Based on a first specific small-molecule inhibitor targeting Hsp90-Cdc37 PPI (), which was previously reported by our group, we conducted a preliminary investigation of the structure-activity relationships and pharmacodynamic evaluations to improve the potency and drug-like properties. Here, our efforts resulted in the currently best inhibitor with improved binding affinity ( = 0.5 μM) and cellular inhibitory activity (IC = 1.73 μM). Both in vitro and in vivo assays revealed that could efficiently block the Hsp90-Cdc37 interaction to specifically inhibit kinase clients of Hsp90. Furthermore, showed ideal physiochemical properties with favorable stability, leading to an oral efficacy in vivo.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01659DOI Listing
February 2020

Recent progress in the development of small molecule Nrf2 activators: a patent review (2017-present).

Expert Opin Ther Pat 2020 Mar 6;30(3):209-225. Epub 2020 Feb 6.

State Key Laboratory of Natural Medicines, and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.

: The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is the first line of defense against a plethora of environmental or endogenous deviations in redox metabolism, proteostasis, inflammation, etc. Therefore, pharmacological activation of Nrf2 is a potential therapeutic approach for several diseases related to oxidative stress and inflammation, such as cancer, cardiovascular, and neurodegenerative diseases.: The authors first describe the biological function of Nrf2 and the molecular regulatory mechanism of Keap1-Nrf2-ARE ((Kelch-like ECH-Associating protein 1)-Nrf2-(antioxidant response element)). Then, they review recent progress of covalent activators and non-covalent Keap1-Nrf2 protein-protein interaction (PPI) inhibitors from patents and publications in 2017-present, consisting of new chemical molecules, structure optimization of reported activators and progress in preclinical or clinical trials.: Despite significant achievements in the development of Nrf2 activators, the selectivity is the primary consideration. Due to reacting with redox-sensitive cysteines in proteins except for Keap1, electrophilic activators often exhibit off-target effects. For Keap1-Nrf2 PPI inhibitors, how to enhance efficacy and/or penetrate blood-brain barrier (BBB) to reach central nervous system (CNS) is also challenging. Fragment-based drug discovery (FBDD), carboxylic acid bioisosteric replacement and prodrug approach might be used to circumvent this challenge. Moreover, the possibility of cancer risk caused by Nrf2 activation needs to be considered carefully.
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http://dx.doi.org/10.1080/13543776.2020.1715365DOI Listing
March 2020

Corrigendum to "Inhibitory effects of wogonin on the invasion of human breast carcinoma cells by downregulating the expression and activity of matrix metalloproteinase-9" [Toxicology 282 (2011) 122-128].

Toxicology 2019 Nov 18;427:152288. Epub 2019 Oct 18.

Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China. Electronic address:

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http://dx.doi.org/10.1016/j.tox.2019.152288DOI Listing
November 2019

Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer.

Sci Adv 2019 09 18;5(9):eaax2277. Epub 2019 Sep 18.

State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.

Disrupting the interactions between Hsp90 and Cdc37 is emerging as an alternative and specific way to regulate the Hsp90 chaperone cycle in a manner not involving adenosine triphosphatase inhibition. Here, we identified DDO-5936 as a small-molecule inhibitor of the Hsp90-Cdc37 protein-protein interaction (PPI) in colorectal cancer. DDO-5936 disrupted the Hsp90-Cdc37 PPI both in vitro and in vivo via binding to a previously unknown site on Hsp90 involving Glu, one of the binding determinants for the Hsp90-Cdc37 PPI, leading to selective down-regulation of Hsp90 kinase clients in HCT116 cells. In addition, inhibition of Hsp90-Cdc37 complex formation by DDO-5936 resulted in a remarkable cyclin-dependent kinase 4 decrease and consequent inhibition of cell proliferation through Cdc37-dependent cell cycle arrest. Together, our results demonstrated DDO-5936 as an identified specific small-molecule inhibitor of the Hsp90-Cdc37 PPI that could be used to comprehensively investigate alternative approaches targeting Hsp90 chaperone cycles for cancer therapy.
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http://dx.doi.org/10.1126/sciadv.aax2277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750927PMC
September 2019

Design, synthesis and evaluation of phthalazinone thiohydantoin-based derivative as potent PARP-1 inhibitors.

Bioorg Chem 2019 10 3;91:103181. Epub 2019 Aug 3.

State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Two new series of compounds were designed and synthesized as potent PARP-1 inhibitors. These compounds were evaluated for PARP-1 enzyme and cellular inhibitory activities. All efforts lead to the identification of 9k (named as LG-12) with efficient potency both for PARP-1 and BRCA1 deficient MDA-MB-436 cells. Additionally, the novel PARP-1 inhibitor LG-12 is an efficient chemosensitizer, which could potentiate the anti-cancer effect of TMZ. Our data presented herein provide a comprehensive preclinical in vitro evaluation of the potential therapeutic efficacy and potency of chemotherapeutic agent-PARP-1 inhibitor combinations for LG-12. The combined results indicated that LG-12 could be a promising candidate for further study.
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http://dx.doi.org/10.1016/j.bioorg.2019.103181DOI Listing
October 2019

Photoactivatable Prolyl Hydroxylase 2 Inhibitors for Stabilizing the Hypoxia-Inducible Factor with Light.

J Med Chem 2019 08 25;62(16):7583-7588. Epub 2019 Jun 25.

State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization , China Pharmaceutical University , Nanjing 210009 , China.

HIF prolyl hydroxylase 2 (PHD2) inhibitors represent a novel approach for treating HIF-related diseases. This study reports the first application of photoremovable protecting group to the photoactivatable inhibitor () of PHD2. It allows the inhibitory activity for PHD2 to be controlled by light irradiation, subsequently stabilizing HIF and promoting expression of the target gene. Light activation to stabilize HIF offers promising potentials for the tissue-specific therapies for HIF-related disease by light irradiation onto target tissues.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00688DOI Listing
August 2019

Design and synthesis of novel steroidal imidazoles as dual inhibitors of AR/CYP17 for the treatment of prostate cancer.

Steroids 2019 10 15;150:108384. Epub 2019 Mar 15.

Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address:

Both AR and CYP17 are important targets for blocking androgen signaling, and it has been accepted that multifunctional drugs have a low risk of drug resistance in the treatment of cancer. Thus, herein a series of steroidal imidazoles were designed, synthesized and evaluated as dual AR/CYP17 ligands. Several compounds displayed good biological profiles in both enzymatic and cellular assays. SAR studies showed that introducing oximino at the C-3 position of steroidal scaffold is beneficial to the enhancement of AR antagonistic activity. Among these compounds, the most potent compound 13a exhibited the best AR inhibition (IC = 0.5 μM) that was 27-fold increase compared with the hit compound 5 as well as comparable CYP17 inhibition (IC = 11 μM). Additionally, 13a displayed promising anti-proliferative effects on LNCap cell lines with the IC value of 23 μM which was superior to positive control Flutamide (IC = 28 μM). Furthermore, the docking results of 13a revealed that the oxygen atom at the position of C-3 connected to the heme of CYP17, which may be helpful for its satisfactory dual-target inhibition. In summary, this study provides an efficient strategy for multi-targeting drug discovery in the treatment of prostate cancer.
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http://dx.doi.org/10.1016/j.steroids.2019.03.003DOI Listing
October 2019

Design, synthesis and biological evaluation of novel 2-phenyl pyrimidine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors.

Medchemcomm 2019 Feb 16;10(2):294-299. Epub 2019 Jan 16.

Jiangsu Key Laboratory of Drug Design and Optimization , China Pharmaceutical University , Nanjing 210009 , China . Email: ; ; Tel: +86 025 83271096.

BTK is an effective target for the treatment of B-cell malignant tumors and autoimmune diseases. In this work, a series of 2-phenyl pyrimidine derivatives were prepared and their preliminary activities on B-cell leukemia cells as well as the BTK enzyme were determined. The results showed that compound displayed the best inhibitory activity on BTK with an inhibition rate of 82.76% at 100 nM and excellent anti-proliferation activity on three B-cell leukemia lines (IC = 3.66 μM, 6.98 μM, and 5.39 μM against HL60, Raji and Ramos, respectively). Besides, the flow cytometry analysis results indicated that inhibited the proliferation of the Raji cells in a dose- and time-dependent manner, and blocked the Ramos cells at the G0/G1 phase, which is in accordance with the positive control ibrutinib. The mechanism investigation demonstrated that could inhibit the phosphorylation of BTK and its downstream substrate phospholipase γ2 (PLCγ2). All these results showed that was a promising lead compound that merited further optimization as a novel class of BTK inhibitor for the treatment of B-cell lymphoblastic leukemia.
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http://dx.doi.org/10.1039/c8md00413gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390688PMC
February 2019

Medicinal chemistry of metal chelating fragments in metalloenzyme active sites: A perspective.

Eur J Med Chem 2019 Mar 14;165:172-197. Epub 2019 Jan 14.

Sate Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Chemistry, School of Science, China Pharmaceutical University, Nanjing, 211198, China. Electronic address:

Numerous metal-containing enzymes (metalloenzymes) have been considered as drug targets related to diseases such as cancers, diabetes, anemia, AIDS, malaria, bacterial infection, fibrosis, and neurodegenerative diseases. Inhibitors of the metalloenzymes have been developed independently, most of which are mimics of substrates of the corresponding enzymes. However, little attention has been paid to the interactions between inhibitors and active site metal ions. This review is focused on different metal binding fragments and their chelating properties in the metal-containing active binding pockets of metalloenzymes. We have enumerated over one hundred of inhibitors targeting various metalloenzymes and identified over ten kinds of fragments with different binding patterns. Furthermore, we have investigated the inhibitors that are undergoing clinical evaluation in order to help looking for more potential scaffolds bearing metal binding fragments. This review will provide deep insights for the rational design of novel inhibitors targeting the metal-containing binding sites of specific proteins.
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http://dx.doi.org/10.1016/j.ejmech.2019.01.018DOI Listing
March 2019

Small-Molecule Modulators of the Hypoxia-Inducible Factor Pathway: Development and Therapeutic Applications.

J Med Chem 2019 06 8;62(12):5725-5749. Epub 2019 Feb 8.

State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization , China Pharmaceutical University , Nanjing 210009 , China.

Hypoxia-inducible factor (HIF) is a central regulator involved in detection and adaption to cellular oxygen stress through regulation of the hypoxic transcriptional program in angiogenesis, erythropoiesis, and metabolism. The HIF pathway is involved in many diseases. On one hand, overexpression of the HIF pathway is associated with solid tumors such as renal cell carcinoma (RCC). On the other hand, suppression of the HIF pathway is correlated with inflammatory, anemia, and other hypoxic-ischemic diseases. Therefore, modulation of the HIF pathway has been perceived as a promising strategy for treating HIF-related diseases. Recent advances in understanding of the biochemistry underlying the HIF pathway have stimulated small-molecule drugs development, and therapeutically, manipulation of the HIF-mediated response has been shown to have considerable medicinal potential. This review will summarize and provide insight into recent advances in research that have expanded our knowledge of the HIF pathway, including its structural basis and biology, small-molecule modulators of the pathway, including inhibitors and activators, and the potential therapeutic applications of these modulators.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01596DOI Listing
June 2019

Discovery of Nonquinone Substrates for NAD(P)H: Quinone Oxidoreductase 1 (NQO1) as Effective Intracellular ROS Generators for the Treatment of Drug-Resistant Non-Small-Cell Lung Cancer.

J Med Chem 2018 12 10;61(24):11280-11297. Epub 2018 Dec 10.

State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization , China Pharmaceutical University , Nanjing , 210009 , China.

The elevation of oxidative stress preferentially in cancer cells by efficient NQO1 substrates, which promote ROS generation through redox cycling, has emerged as an effective strategy for cancer therapy, even for treating drug-resistant cancers. Here, we described the identification and structural optimization studies of the hit compound 1, a new chemotype of nonquinone substrate for NQO1 as an efficient ROS generator. Further structure-activity relationship studies resulted in the most active compound 20k, a tricyclic 2,3-dicyano indenopyrazinone, which selectively inhibited the proliferation of NQO1-overexpressing A549 and A549/Taxol cancer cells. Furthermore, 20k dramatically elevated the intracellular ROS levels through NQO1-catalyzed redox cycling and induced PARP-1-mediated cell apoptosis in A549/Taxol cells. In addition, 20k significantly suppressed the growth of A549/Taxol xenograft tumors in mice with no apparent toxicity observed in vivo. Together, 20k acts as an efficient NQO1 substrate and may be a new option for the treatment of NQO1-overexpresssing drug-resistant NSCLC.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01424DOI Listing
December 2018

Synthesis and biological evaluation of 3-aryl-quinolin derivatives as anti-breast cancer agents targeting ERα and VEGFR-2.

Eur J Med Chem 2019 Jan 19;161:445-455. Epub 2018 Oct 19.

Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address:

SERMs are a series of important small molecular compounds to modulate estrogen receptor, such as tamoxifen. Although these drugs have showed great benefits in the treatment of breast cancer, the risk of endometrial cancer and endocrine resistance restrict their use. The reasonable designing of multi-target drugs can decrease the side effects and improve the tolerance of antineoplastic agents Studies have identified that VEGFR-2 plays a pivotal role in tumor angiogenesis and drug resistance. Besides, a combination of Tamoxifen and low dose of a VEGFR-2 inhibitor was reported to maximize therapeutic efficacy as well as to retard SERM resistant tumor growth. In this work, a series of 3-aryl-quinolin derivatives were designed to target to ERα and VEGFR-2 to eliminate the disadvantages of SERMs. We identified that compounds 12f and 13f displayed highly ERα binding affinities as well as relative intensity VEGFR-2 inhibitory activities. Moreover, this two compounds exhibited excellent anti-proliferative activities against MCF-7 and HUVEC cell lines with low micromolar IC (1-8 μM). A further study confirmed that compound 13f can reduce the expression of PgR mRNA, arrest cell cycle in MCF-7 breast cancer cells, and restrain the cell migration. Overall, based on the biological activities data, 13f can be chosen as a potential anti-cancer lead compound for further studying.
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http://dx.doi.org/10.1016/j.ejmech.2018.10.045DOI Listing
January 2019

Structure-guided design and synthesis of isoflavone analogs of GW4064 with potent lipid accumulation inhibitory activities.

Bioorg Med Chem Lett 2018 12 15;28(23-24):3726-3730. Epub 2018 Oct 15.

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Our group has previously reported a series of isoflavone derivatives with antidyslipidemic activity. With this background, a series of isoflavone analogs of GW4064 were designed, synthesized and evaluated the lipid-lowering activity of analogs. As a result, most of compounds significantly reduced the lipid accumulation in 3T3-L1 adipocytes and four of them (10a, 11, 15c and 15d) showed stronger inhibitory than GW4064. The most potent compound 15d exhibited promising agonistic activity for FXR in a cell-based luciferase reporter assay. Meanwhile, 15d up-regulated FXR, SHP and BSEP gene expression and down-regulated the mRNA expression of lipogenesis gene SREBP-1c. Besides, an improved safety profile of 15d was also observed in a HepG2 cytotoxicity assay compared with GW4064. The obtained biological results were further confirmed by a molecular docking study showing that 15d fitted well in the binding pocket of FXR and interacted with some key residues simultaneously.
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http://dx.doi.org/10.1016/j.bmcl.2018.10.021DOI Listing
December 2018

Design and synthesis of benzofuro[3,2-b]pyridin-2(1H)-one derivatives as anti-leukemia agents by inhibiting Btk and PI3Kδ.

Bioorg Med Chem 2018 08 29;26(15):4537-4543. Epub 2018 Jul 29.

Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address:

Btk inhibitors and PI3Kδ inhibitors play crucial roles in the treatment of leukemia, and studies confirmed that the synergetic inhibition against Btk and PI3Kδ could gain an optimal response. Herein, a series of novel benzofuro[3,2-b]pyridin-2(1H)-one derivatives were designed and synthesized as dual Btk/PI3Kδ kinases inhibitors for the treatment of leukemia. Studies indicated that most compounds could suppress the proliferation of multiple leukemia or lymphoma cells (Raji, HL60 and K562 cells) at low micromolar concentrations in vitro. Further kinase assays identified several compounds could simultaneously inhibit Btk kinase and PI3Kδ kinase. Thereinto, compound 16b exhibited the best inhibitory activity (Btk: IC = 139 nM; PI3Kδ: IC = 275 nM) and showed some selectivity against PI3Kδ compared to PI3Kβ/γ. Finally, the SAR of target compounds was preliminarily discussed combined with docking results. In brief, 16b possessed of the potency for the further optimization as anti-leukemia drugs by inhibiting simultaneously Btk kinase and PI3Kδ kinase.
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http://dx.doi.org/10.1016/j.bmc.2018.07.047DOI Listing
August 2018

Lipid accumulation inhibitory activities of novel isoxazole-based chenodeoxycholic acids: Design, synthesis and preliminary mechanism study.

Bioorg Med Chem Lett 2018 09 17;28(17):2879-2884. Epub 2018 Jul 17.

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

In continuation of our drug discovery program on hyperlipidemia, a series of novel isoxazole-chenodeoxycholic acid hybrids were designed, synthesized and evaluated for their lipid-lowering effects. Preliminary screening of all the synthesized compounds was done by using a 3T3-L1 adipocyte model, in which the most active compound 16b could significantly reduce the lipid accumulation up to 30.5% at a nontoxic concentration 10 μM. Further mechanism studies revealed that 16b blocked lipid accumulation via activating FXR-SHP signaling pathway, efficiently down-regulated the expression of key lipogenesis regulator SREBP-1c.
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http://dx.doi.org/10.1016/j.bmcl.2018.07.026DOI Listing
September 2018

Lipid reducing activity of novel cholic acid (CA) analogs: Design, synthesis and preliminary mechanism study.

Bioorg Chem 2018 10 5;80:396-407. Epub 2018 Jul 5.

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Bile acids, initially discovered as endogenous ligands of farnesoid X receptor (FXR), play a central role in the regulation of triglyceride and cholesterol metabolism and have recently emerged as a privileged structure for interacting with nuclear receptors relevant to a large array of metabolic processes. In this paper, phenoxy containing cholic acid derivatives with excellent drug-likeness have been designed, synthesized, and assayed as agents against cholesterol accumulation in Raw264.7 macrophages. The most active compound 14b reduced total cholesterol accumulation in Raw264.7 cells up to 30.5% at non-toxic 10 μM and dosage-dependently attenuated oxLDL-induced foam cell formation. Western blotting and qPCR results demonstrate that 14b reduced both cholesterol and lipid in Raw264.7 cells through (1) increasing the expression of cholesterol transporters ABCA1 and ABCG1, (2) accelerating ApoA1-mediated cholesterol efflux. Through a cell-based luciferase reporter assay and molecular docking analysis, LXR was identified as the potential target for 14b. Interestingly, unlike conventional LXR agonist, 14b did not increase lipogenesis gene SREBP-1c expression. Overall, these diverse properties disclosed herein highlight the potential of 14b as a promising lead for further development of multifunctional agents in the therapy of cardiovascular disease.
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http://dx.doi.org/10.1016/j.bioorg.2018.07.002DOI Listing
October 2018