Publications by authors named "Hongqi Tian"

30 Publications

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Radioprotective effects and mechanism of HL-003 on radiation-induced salivary gland damage in mice.

Sci Rep 2022 May 19;12(1):8419. Epub 2022 May 19.

Department of Oral Medicine, Tianjin Stomatological Hospital, School of Medicine, Nankai University, Tianjin, 300041, China.

Ionizing radiation (IR) can cause damage to the structure and function of salivary glands. Our research group independently synthesized the ROS scavenger, HL-003. The aim of this study was to explore the protective effects and underlying mechanisms of HL-003 on radiation-induced salivary gland injury. Salivary flow rate measurement, H&E staining, immunohistochemistry, FRAP, TUNEL, and western blotting were used to evaluate the radioprotective effect on salivary glands. The results showed that HL-003 protected the salivary secretion function by protecting the AQP-5 protein, on the salivary epithelial cell membrane, from IR damage. HL-003 reduced oxidative stress in the salivary gland by regulating the expression of ROS-related proteins NOX4, SOD2, and 8-OHdG. Furthermore, HL-003 downregulated the expression of p-p53, Bax, caspase 3, and caspase 9, and upregulated the expression of Bcl-2, suggesting that it could inhibit the activation of p53 to reduce cell apoptosis. In conclusion, HL-003 is an effective radioprotector that prevents damage of the radiation-induced salivary gland.
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http://dx.doi.org/10.1038/s41598-022-12581-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120142PMC
May 2022

Protective mechanism of a novel aminothiol compound on radiation-induced intestinal injury.

Int J Radiat Biol 2022 May 27:1-11. Epub 2022 May 27.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin, China.

Purpose: With the development of nuclear technology and radiotherapy, the risk of radiation injury has been increasing. Therefore, it is important to find an effective radiation-protective agent. In this study, we designed and synthesized a novel compound called compound , of which the radioprotective effect and mechanism were studied.

Materials And Methods: Before being exposed to ionizing radiation, mice were pretreated with compound . The 30-day mortality assay, hematoxylin-eosin staining, and immunohistochemistry staining assay were performed to evaluate the anti-radiation effect of the compound . TUNEL and immunofluorescence assays were conducted to study the anti-radiation mechanism of compound .

Results: Compared to the IR + vehicle group, the 30-day survival rate of mice treated with 25 mg/kg of compound was significantly improved after 8 Gy total body irradiation. In the morphological study of the small intestine, we found that compound could maintain crypt-villus structures in the irradiated mice. Further immunohistochemical staining displayed that compound could improve the survival of Lgr5 cells, ki67 cells, and lysozyme cells. The results of TUNEL and immunofluorescence assays showed that compound could decrease the expression of apoptosis-related caspase-8/-9, γ-H2AX, Bax, and p53.

Conclusions: These results indicate that compound exerts its effects by maintaining structure and function of small intestine. It also reduces DNA damage, promotes crypt proliferation and differentiation. Moreover, it may enhance the anti-apoptotic ability of small intestinal tissue by inhibiting the activation of p53 and blocking the caspase cascade reaction. Compound can protect the intestinal tract from post-radiation damage, it is thus a new and effective protective agent of radiation.
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http://dx.doi.org/10.1080/09553002.2022.2074163DOI Listing
May 2022

Design, Synthesis, and Biological Evaluation of a Novel Aminothiol Compound as Potential Radioprotector.

Oxid Med Cell Longev 2021 21;2021:4714649. Epub 2021 Aug 21.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin 300192, China.

The risk of radiation damage has increased with the rapid development of nuclear technology and radiotherapy. Hence, research on radioprotective agents is of utmost importance. In the present study, a novel aminothiol compound 12, containing a linear alkylamino backbone and three terminal thiols, was synthesized. Owing to the appropriate capped groups in the chains, it has an improved permeability and oral bioavailability compared to other radioprotective agents. Oral administration of compound 12 improved the survival of mice that received lethal doses of -irradiation. Experimental results demonstrated that compound 12 not only mitigated total body irradiation-induced hematopoietic injury by increasing the frequencies of hematopoietic stem and progenitor cells but also prevented abdominal irradiation-induced intestinal injury by increasing the survival of Lgr5 intestinal cells, lysozyme Paneth cells, and Ki67 cells. In addition, compound 12 decreased oxidative stress by upregulating the expression of Nrf2 and NQO1 and downregulating the expression of NOX1. Further, compound 12 inhibited -irradiation-induced DNA damage and alleviated G2/M phase arrest. Moreover, compound 12 decreased the levels of p53 and Bax and increased the level of Bcl-2, demonstrating that it may suppress radiation-induced apoptosis via the p53 pathway. These results indicate that compound 12 has the possibility of preventing radiation injury and can be a potential radioprotector for clinical applications.
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http://dx.doi.org/10.1155/2021/4714649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405339PMC
January 2022

Synthesis and radioprotective effects of novel hybrid compounds containing edaravone analogue and 3-n-butylphthalide ring-opening derivatives.

J Cell Mol Med 2021 06 8;25(12):5470-5485. Epub 2021 May 8.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin, China.

As the potential risk of radiation exposure is increasing, radioprotectors studies are gaining importance. In this study, novel hybrid compounds containing edaravone analogue and 3-n-butylphthalide ring-opening derivatives were synthesized, and their radioprotective effects were evaluated. Among these, compound 10a displayed the highest radioprotective activity in IEC-6 and HFL-1 cells. Its oral administration increased the survival rates of irradiated mice and alleviated total body irradiation (TBI)-induced hematopoietic damage by mitigating myelosuppression and improving hematopoietic stem/progenitor cell frequencies. Furthermore, 10a treatment prevented abdominal irradiation (ABI)-induced structural damage to the small intestine. Experiment results demonstrated that 10a increased the number of Lgr5 intestinal stem cells, lysozyme Paneth cells and Ki67 transient amplifying cells, and reduced apoptosis of the intestinal epithelium cells in irradiated mice. Moreover, in vitro and in vivo studies demonstrated that the radioprotective activity of 10a is associated to the reduction of oxidative stress and the inhibition of DNA damage. Furthermore, compound 10a downregulated the expressions of p53, Bax, caspase-9 and caspase-3, and upregulated the expression of Bcl-2, suggesting that it could prevent irradiation-induced intestinal damage through the p53-dependent apoptotic pathway. Collectively, these findings demonstrate that 10a is beneficial for the prevention of radiation damage and has the potential to be a radioprotector.
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http://dx.doi.org/10.1111/jcmm.16557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184683PMC
June 2021

Neuroprotective Effect of a New Free Radical Scavenger HL-008 in an Ischemia-Reperfusion Injury Rat Model.

Neuroscience 2021 06 27;465:105-115. Epub 2021 Apr 27.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 238, Baidi Road, Tianjin, China. Electronic address:

Oxidative stress plays a critical role in cerebral ischemia-reperfusion injury. We have previously developed a powerful antioxidant, HL-008. This study aimed to investigate the neuroprotective function of HL-008. HL-008 efficacy in vitro and in vivo was evaluated using a PC-12 cell oxidative stress model induced by hydrogen peroxide and a rat model of middle cerebral artery occlusion, respectively. The MTT assay was used to analyze cell viability. 2,3,5-Triphenyltetrazolium chloride and Hematoxylin and Eosin staining, immunofluorescence, western blot, and proteomics were used to evaluate the infarction volume, brain tissue morphology, apoptosis, inflammation, and related pathways. Indicators related to oxidative levels were also detected. HL-008 significantly reduced the cerebral infarction volume induced by ischemia-reperfusion, improved the neurological score, alleviated oxidative stress and inflammation in the brain tissue, reduced glial cell activation, inhibited brain tissue apoptosis by influencing multiple signaling pathways, and had a neuroprotective effect. If HL-008 is successfully developed, it could significantly improve stroke patients' quality of life.
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http://dx.doi.org/10.1016/j.neuroscience.2021.04.012DOI Listing
June 2021

Design, synthesis, and neuroprotective effects of novel hybrid compounds containing edaravone analogue and 3-n-butylphthalide ring-opened derivatives.

Biochem Biophys Res Commun 2021 06 8;556:99-105. Epub 2021 Apr 8.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin, 300192, China. Electronic address:

To develop anti-ischemic stroke drugs with higher blood-brain barrier (BBB) penetrating capability and neuroprotective activity, a series of hybrid compounds containing edaravone analogue and 3-n-butylphthalide (NBP) ring-opened derivatives were synthesized and biologically evaluated. Among them, compound 10a displayed the highest protective activity in SH-SY5Y cells against oxygen and glucose deprivation (OGD) and HO insults. Experiment results indicated that 10a could inhibit platelet aggregation via the synergistic action of the edaravone analogue and NBP, and its oral administration protected the rats against ischemia/reperfusion-induced brain injury. Moreover, 10a effectively inhibited apoptosis and reduced oxidative stress in OGD-exposed cells. Further analysis suggested that 10a might alleviate oxidative damage in SH-SY5Y cells via the modulation of the Nrf2 pathway. Collectively, these findings demonstrate that 10a can emerge as a potential candidate drug for the treatment of ischemic stroke.
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http://dx.doi.org/10.1016/j.bbrc.2021.03.171DOI Listing
June 2021

Oral Codelivery of WR-1065 Using Curcumin-Linked ROS-Sensitive Nanoparticles for Synergistic Radioprotection.

ACS Biomater Sci Eng 2021 06 7;7(6):2496-2507. Epub 2021 Apr 7.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300192, China.

Protecting the body from radiation damage is a huge medical challenge. Amifostine and curcumin are both effective radioprotectants, but their use has been greatly restricted due to various reasons including low bioavailability. Nanoscale drug delivery systems of poly(ethylene glycol)-poly(ε-caprolactone) copolymers can improve the bioavailability of drugs due to excellent biocompatibility, biodegradability, and long circulation characteristics. In this study, a new reactive oxygen species-sensitive nanocarrier fabricated by linking curcumin and thioketal to poly(ethylene glycol)-poly(ε-caprolactone) polymer was used for delivery of WR-1065 (the active ingredient of amifostine). The content of curcumin in this polymer was about 7.6%, and the drug loading of WR-1065 was 44%. The WR-1065-loaded nanoparticles (NPs) had an average size of 128.6 nm and uniform spherical morphology. These WR-1065-loaded NPs reduced the metabolism of curcumin and WR-1065 in the gastrointestinal tract and could be well absorbed by cells and distributed to multiple organs. Compared with a single drug, oral administration of WR-1065-loaded NPs demonstrated obvious radioprotective effects on the hematopoietic system and prevented intestinal injury. The 30-day survival rate after half-lethal dose (7.2 Gy) of total body irradiation was 100%. In general, WR-1065-loaded NPs improved the oral bioavailability of WR-1065 and curcumin. This multifunctional nanocarrier provides a possibility for combination therapy in treating ionizing radiation damage.
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http://dx.doi.org/10.1021/acsbiomaterials.0c01780DOI Listing
June 2021

Preclinical Evaluation of Safety, Pharmacokinetics, Efficacy, and Mechanism of Radioprotective Agent HL-003.

Oxid Med Cell Longev 2021 19;2021:6683836. Epub 2021 Feb 19.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Science, Tianjin 300192, China.

Amifostine is a radioprotector with high efficacy but poor safety, short half-life, no oral formulation, and poor compliance, which limits its application. With the increasing risk of exposure to radiation, the development of new radioprotective agents is critical. We previously synthesized a new amifostine derivative, the small molecule compound HL-003. In this study, we focused on evaluating the radioprotective properties of HL-003. Using the 2,2-diphenyl-1-picrylhydrazyl assay, we initially confirmed HL-003 as a strong antioxidant and demonstrated that its free radical scavenging activity was stronger than that of amifostine. Then, we performed an acute toxicity test, a 28-day toxicity test, a 30-day survival rate test, and a pharmacokinetic study, all of which provided aggregate evidence that HL-003 functioned as a small molecule radioprotector with high efficacy, a favorable safety profile, a long half-life, and oral administration. The intestinal radioprotective mechanism of HL-003 was explored in male C57 mice after abdominal irradiation by analyzing intestinal tissue samples with hematoxylin-eosin staining, immunohistochemistry, TUNEL staining, and immunofluorescence detection. The results showed that HL-003 protected intestinal DNA from radiation damage and suppressed the expression of phosphorylated histone H2AX, phosphorylated p53, and the apoptosis-related proteins caspase-8 and caspase-9, which contributed to maintaining the normal morphology of the small intestine and provided insights into the mechanism of radioprotection. Thus, HL-003 is a small molecule radioprotector with a potential application in radiation medicine.
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http://dx.doi.org/10.1155/2021/6683836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914087PMC
May 2021

Polycysteine as a new type of radio-protector ameliorated tissue injury through inhibiting ferroptosis in mice.

Cell Death Dis 2021 02 18;12(2):195. Epub 2021 Feb 18.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science & Peking Union Medical College, 300000, Tianjin, China.

Amifostine has been the only small molecule radio-protector approved by FDA for decades; however, the serious adverse effects limit its clinical use. To address the toxicity issues and maintain the good potency, a series of modified small polycysteine peptides had been prepared. Among them, compound 5 exhibited the highest radio-protective efficacy, the same as amifostine, but much better safety profile. To confirm the correlation between the radiation-protective efficacy and the DNA binding capability, each of the enantiomers of the polycysteine peptides had been prepared. As a result, the L-configuration compounds had obviously higher efficacy than the corresponding D-configuration enantiomers; among them, compound 5 showed the highest DNA binding capability and radiation-protective efficacy. To our knowledge, this is the first study that has proved their correlations using direct comparison. Further exploration of the mechanism revealed that the ionizing radiation (IR) triggered ferroptosis inhibition by compound 5 could be one of the pathways for the protection effect, which was different from amifostine. In summary, the preliminary result showed that compound 5, a polycysteine as a new type of radio-protector, had been developed with good efficacy and safety profile. Further study of the compound for potential use is ongoing.
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http://dx.doi.org/10.1038/s41419-021-03479-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977147PMC
February 2021

Design and evaluation of pH-responsive hydrogel for oral delivery of amifostine and study on its radioprotective effects.

Colloids Surf B Biointerfaces 2020 Nov 18;195:111200. Epub 2020 Jun 18.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China. Electronic address:

The purpose of this study was to develop a novel pH-sensitive hydrogel which was used to regulate the acute radiation syndrome (ARS). The hydrogel was fabricated by grafting polycaprolactone onto methacrylic acid copolymer (MAC-g-PCL). Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (H NMR) confirmed the obtaining of MAC-g-PCL hydrogel. The hydrogel was pH-sensitive, at pH 1.2, it was compact hydrogel, but at pH7.4, it was dissolved solution. Its inner 3D morphology was observed by scanning electron microscope (SEM). Cell experiments indicated that the MAC-g-PCL hyrogel was out of cytotoxicity. The release profile of amifostine showed that small amount drug release in simulated gastric fluid (pH 1.2) and burst release in simulated intestinal fluid (pH 7.4). Thus, the pH-sensitive hydrogels could protect amifostine from enzymatic degradation in acidic stomach and deliver effectively in the intestine. The radioprotective efficacy was determined by peripheral complete blood parameters and 30-day survival study in mice acutely exposed to 4 Gy γ-ray total body irradiation. Results suggested that oral administration MAC-g-PCL/Ami before total body irradiation protected the mice from hematopoietic ARS and enhanced their survival. Furthermore, in vivo bio-distribution studies indicated that the drug could be sustained delivered at intestinal tract and entered the bloodstream. These results demonstrated that oral administration of amifostine hydrogel provided effective radioprotection to reduce the ARS injury.
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http://dx.doi.org/10.1016/j.colsurfb.2020.111200DOI Listing
November 2020

A New Compound with Increased Antitumor Activity by Cotargeting MEK and Pim-1.

iScience 2020 Jul 10;23(7):101254. Epub 2020 Jun 10.

Guangdong Provincial Key Laboratory of Breast Cancer Diagnosis and Treatment, Shantou University Medical College Cancer Hospital, 7 Raoping Road, Shantou, Guangdong 515031, China. Electronic address:

Feedback circuits are one of the major causes underlying tumor resistance. Thus, compounds that target one oncogenic pathway with simultaneously blocking its compensatory pathway will be of great value for cancer treatment. Here, we develop a new MEK inhibitor designated as KZ-02 that exhibits unexpectedly higher cytotoxicity than its starting compound AZD6244, a well-known MEK inhibitor, in colorectal cancer (CRC). Subsequent kinase selectivity study identified Pim-1 as an additional cellular target for KZ-02. Further studies showed that AZD6244 and Pim-1 1 (a Pim-1 inhibitor) have a synergistic effect on CRC suppression. Mechanistic study revealed that MEK inhibition by AZD6244 leads to increased Pim-1 expression, which could be a general mechanism behind the compromised cell-killing activity of MEK inhibitors. KZ-02, despite increasing Pim-1 mRNA expression, simultaneously promotes Pim-1 proteasomal degradation. Therefore, we uncover a new MEK inhibitor KZ-02 with significantly enhanced antitumor activity by co-targeting MEK and Pim-1.
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http://dx.doi.org/10.1016/j.isci.2020.101254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322072PMC
July 2020

Protective effects of new aryl sulfone derivatives against radiation-induced hematopoietic injury.

J Radiat Res 2020 May;61(3):388-398

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300192, China.

The hematopoietic system is sensitive to radiation. In this research, new aryl sulfone derivatives (XH-201 and XH-202) containing a nitrogen heterocycle were designed and synthesized and their radio-protective efficacies with regard to the hematopoietic system were evaluated. XH-201 administration significantly increased the survival rate of mice after 8.0 Gy total body irradiation (TBI). The results showed that XH-201 treatment not only increased the white blood cells, platelets counts and the percentage of hematopoietic progenitor cells and hematopoietic stem cells in mice exposed to 4.0 Gy TBI but also decreased DNA damage, as determined by flow cytometric analysis of histone H2AX phosphorylation. In addition, our data demonstrated that XH-201 decreased the mitochondrial reactive oxygen species (ROS) levels in hematopoietic cells. Overall, these data suggest that XH-201 is beneficial for the protection of the hemoatopoietic system against radiation-induced injuries.
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http://dx.doi.org/10.1093/jrr/rraa009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299261PMC
May 2020

1,4-Dithiothreitol treatment ameliorates hematopoietic and intestinal injury in irradiated mice: Potential application of a treatment for acute radiation syndrome.

Int Immunopharmacol 2019 Nov 15;76:105913. Epub 2019 Oct 15.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300192, China. Electronic address:

Radiation exposure poses a significant threat to public health, which can lead to acute hematopoietic system and intestinal system injuries due to their higher radiation sensitivity. Hence, antioxidants and thiol-reducing agents could have a potential protective effect against this complication. The dithiol compound 1,4-dithiothreitol (DTT) has been used in biochemistry, peptide/protein chemistry and clinical medicine. However, the effect of DTT on ionizing radiation (IR)-induced hematopoietic injury and intestinal injury are unknown. The current investigation was designed to evaluate the effect of DTT as a safe and clinically applicable thiol-radioprotector in irradiated mice. DTT treatment improved the survival of irradiated mice and ameliorated whole body irradiation (WBI)-induced hematopoietic injury by attenuating myelosuppression and myeloid skewing, increasing self-renewal and differentiation of hematopoietic progenitor cells/hematopoietic stem cells (HPCs/HSCs). In addition, DTT treatment protected mice from abdominal irradiation (ABI)-induced changes in crypt-villus structures and function. Furthermore, treatment with DTT significantly enhanced the ABI-induced reduction in Olfm4 positive cells and offspring cells of Lgr5 stem cells, including lysozyme Paneth cells and Ki67 cells. Moreover, IR-induced DNA strand break damage, and the expression of proapoptotic-p53, Bax, Bak protein and antiapoptotic-Bcl-2 protein were reversed in DTT treated mice, and DTT also promoted small intestine repair after radiation exposure via the p53 intrinsic apoptotic pathway. In general, these results demonstrated the potential of DTT for protection against hematopoietic injury and intestinal injury after radiation exposure, suggesting DTT as a novel effective agent for radioprotection.
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http://dx.doi.org/10.1016/j.intimp.2019.105913DOI Listing
November 2019

Development of ERK1/2 inhibitors as a therapeutic strategy for tumour with MAPK upstream target mutations.

J Drug Target 2020 02 13;28(2):154-165. Epub 2019 Aug 13.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, China.

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylate a variety of substrates that play key roles in promoting cell survival and proliferation. Many inhibitors, acting on upstream of the ERK pathway, exhibit excellent antitumor activity. However, drug-resistant tumour cells invariably emerge after their use due to the reactivation of ERK1/2 signalling. ERK1/2 inhibitors have shown clinical efficacy as a therapeutic strategy for the treatment of tumours with mitogen-activated protein kinase (MAPK) upstream target mutations. These inhibitors may be effective against cancers with altered MAPK upstream pathway and may be used as a possible strategy to overcome acquired resistance to MAPK inhibitors. In this review, we describe the mechanism and types of ERK1/2 inhibitors, summarise the current development status of small-molecule ERK1/2 inhibitors, including the preclinical data and clinical study progress, and discuss the future research directions for the application of ERK1/2 inhibitors.
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http://dx.doi.org/10.1080/1061186X.2019.1648477DOI Listing
February 2020

Metal-Organic Framework (MOF)-Based Drug Delivery.

Curr Med Chem 2020 ;27(35):5949-5969

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China.

Background: Developing a controllable drug delivery system is imperative and important to reduce side effects and enhance the therapeutic efficacy of drugs. Metal-organic frameworks (MOFs) an emerging class of hybrid porous materials built from metal ions or clusters bridged by organic linkers have attracted increasing attention in the recent years owing to the unique physical structures possessed, and the potential for vast applications. The superior properties of MOFs, such as well-defined pore aperture, tailorable composition and structure, tunable size, versatile functionality, high agent loading, and improved biocompatibility, have made them promising candidates as drug delivery hosts. MOFs for drug delivery is of great interest and many very promising results have been found, indicating that these porous solids exhibit several advantages over existing systems.

Objective: This review highlights the latest advances in the synthesis, functionalization, and applications of MOFs in drug delivery, and has classified them using drug loading strategies. Finally, challenges and future perspectives in this research area are also outlined.
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http://dx.doi.org/10.2174/0929867326666190618152518DOI Listing
January 2021

The protective effects of XH-105 against radiation-induced intestinal injury.

J Cell Mol Med 2019 03 20;23(3):2238-2247. Epub 2019 Jan 20.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, China.

Radiation-induced intestinal injury is one of the major side effects in patients receiving radiation therapy. There is no specific treatment for radiation enteritis in the clinic. We designed and synthesized a new compound named XH-105, which is expected to cleave into polyphenol and aminothiol in vivo to mitigate radiation injury. In the following study, we describe the beneficial effects of XH-105 against radiation-induced intestinal injury. C57BL/6J mice were treated by gavage with XH-105 1 hour before total body irradiation (TBI), and the survival rate was monitored. Histological changes were examined, and survival of Lgr5 intestinal stem cells Ki67 cells, villi enterocytes and lysozymes was determined by immunohistochemistry. DNA damage and cellular apoptosis in intestinal tissue were also evaluated. Compared to vehicle-treated mice after TBI, XH-105 treatment significantly enhanced the survival rate, attenuated structural damage of the small intestine, decreased the apoptotic rate, reduced DNA damage, maintained cell regeneration and promoted crypt proliferation and differentiation. XH-105 also reduced the expression of Bax and p53 in the small intestine. These data suggest that XH-105 is beneficial for the protection of radiation-induced intestinal injury by inhibiting the p53-dependent apoptosis signalling pathway.
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http://dx.doi.org/10.1111/jcmm.14159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378229PMC
March 2019

A benzoxazole compound as a novel MEK inhibitor for the treatment of RAS/RAF mutant cancer.

Int J Cancer 2019 07 28;145(2):586-596. Epub 2019 Jan 28.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.

Mutations in RAS/RAF occur in large portion of malignancies and are associated with aggressive clinical behaviors and poor prognosis. Therefore, we developed a novel benzoxazole compound (KZ-001) as a highly potent and selective MEK 1/2 inhibitor. Our efforts were focused on enhancing the activity of the known MEK inhibitor AZD6244 and overcoming the shortcomings existing in current MEK inhibitors. Here we show that compound KZ-001 exhibits approximately 30-fold greater inhibition against BRAF- and KRAS-mutant tumor cells than that of AZD6244. These results were also demonstrated using in vivo xenograft models. Furthermore, pharmacokinetics (PK) analysis was performed for KZ-001, and this compound showed good orally bioavailability (28%) and exposure (AUC = 337 ± 169 ng h/mL). To determine its potential clinical application, the synergistic effect of KZ-001 with other agents was investigated both in vitro and in vivo (xenograft models). KZ-001 exhibited synergistic anti-cancer effect in combination with BRAF inhibitor vemurafenib and a microtubule-stabilizing chemotherapeutic agent docetaxel. In addition, KZ-001 inhibited the MAPK pathway like known MEK inhibitors. In summary, KZ-001, a structurally novel benzoxazole compound, was developed as a MEK inhibitor that has potential for cancer treatment.
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http://dx.doi.org/10.1002/ijc.32119DOI Listing
July 2019

Current Developments in Pt(IV) Prodrugs Conjugated with Bioactive Ligands.

Bioinorg Chem Appl 2018 1;2018:8276139. Epub 2018 Oct 1.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.

To overcome the side effects of and resistance to cisplatin, a variety of Pt(IV) prodrugs were designed and synthesized via different modifications including combination with lipid chains to increase hydrophobicity, conjugation with short peptide chains or nanoparticles to improve drug delivery, or addition of bioactive ligands to the axial positions of Pt(IV) complexes to exert dual-function effects. This review summarizes the recent progress in the development of Pt(IV) prodrugs conjugated with bioactive-targeting ligands, including histone deacetylase inhibitors, p53 agonists, alkylating agents, and nonsteroidal anti-inflammatory agents. Although Pt(IV) complexes that conjugated with bioactive ligands show satisfactory anticancer effects, none has been approved for clinical use. Therefore, we hope that this review will contribute to further study and development of Pt(IV) complexes conjugated with bioactive and other ligands.
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http://dx.doi.org/10.1155/2018/8276139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191961PMC
October 2018

The Protective Effect of New Compound XH-103 on Radiation-Induced GI Syndrome.

Oxid Med Cell Longev 2018 4;2018:3920147. Epub 2018 Jul 4.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China.

Background: Radiation-induced intestinal injury is one of the side effects in patients receiving radiotherapy. The aim of the present study was to investigate the protective effect of XH-103 on radiation-induced small intestinal injury and to explore its mechanism.

Methods: C57BL/6N mice were irradiated and treated with XH-103. Firstly, the survival rate of mice exposed to 9.0 Gy and 11.0 Gy total body irradiation (TBI) was examined. Subsequently, at 3.5 d after IR, the small intestinal morphological changes were examined by HE. The numbers of crypt cells, the villus height, the expression of Ki67 and Lgr5, and the apoptotic cells in the intestinal crypts were examined by immunohistochemistry. Furthermore, the expression of p53 and Bax was analyzed by WB.

Results: Compared to the irradiation group, XH-103 improved the mice survival rate, protected the intestinal morphology of mice, decreased the apoptotic rate of intestinal crypt cells, maintained cell regeneration, and promoted crypt proliferation and differentiation. XH-103 also reduced the expression of p53 and Bax in the small intestine compared to the IR group.

Conclusion: These data demonstrate that XH-103 can prevent radiation-induced intestinal injury, which is beneficial for the protection of radiation injuries.
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http://dx.doi.org/10.1155/2018/3920147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079366PMC
December 2018

N-Heterocyclic Carbene-Protected Ag Nanoparticles Immobilized on Polyacrylonitrile Fiber as Efficient Catalysts for a Three-Component Coupling Reaction.

Chem Asian J 2018 Jun 18;13(12):1561-1569. Epub 2018 May 18.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, 300192, China.

Metal nanoparticles (NPs) are routinely stabilized by the introduction of capping agents or their distribution on supports. In this context, we report the preparation and characterization of N-heterocyclic carbene (NHC)-stabilized silver NPs supported on polyacrylonitrile fiber (PANF). As a result, Ag loadings of up to 8 % and particle sizes of 11.0±3.2 nm were achieved. This novel nanocomposite catalyst demonstrated high activity in addition to excellent stability and reusability in the three-component reaction between alkynes, haloalkanes, and amines. In this system, the AgNPs were stabilized by both a support effect and a ligand effect. The unique NHC-protected AgNP structure and the PANF support provide a synergistic effect in the deprotonation of C -H bonds, with turnover numbers of up to 3500. This catalyst was successfully recycled over eight runs without any significant loss in activity, and with no significant aggregation of the AgNPs. Moreover, implementation of a flow system with [email protected] as catalyst leads to an efficient productivity of 57 mmol h .
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http://dx.doi.org/10.1002/asia.201800154DOI Listing
June 2018

Development of small-molecule immune checkpoint inhibitors of PD-1/PD-L1 as a new therapeutic strategy for tumour immunotherapy.

Authors:
Kui Li Hongqi Tian

J Drug Target 2019 03 20;27(3):244-256. Epub 2018 Feb 20.

a Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine , Chinese Academy of Medical Science & Peking Union Medical College , Tianjin , China.

Cancer immunotherapy has been increasingly utilised to treat advanced malignancies. The signalling network of immune checkpoints has attracted considerable attention. Immune checkpoint inhibitors are revolutionising the treatment options and expectations for patients with cancer. The reported clinical success of targeting the T-cell immune checkpoint receptors PD-1/PD-L1 has demonstrated the importance of immune modulation. Indeed, antibodies binding to PD-1 or PD-L1 have shown remarkable efficacy. However, antibody drugs have many disadvantages, such as their production cost, stability, and immunogenicity and, therefore, small-molecule inhibitors of PD-1 and its ligand PD-L1 are being introduced. Small-molecule inhibitors could offer inherent advantages in terms of pharmacokinetics and druggability, thereby providing additional methods for cancer treatment and achieving better therapeutic effects. In this review, we first discuss how PD-1/PD-L1-targeting inhibitors modulate the relationship between immune cells and tumour cells in tumour immunotherapy. Second, we discuss how the immunomodulatory potential of these inhibitors can be exploited via rational combinations with immunotherapy and targeted therapy. Third, this review is the first to summarise the current clinical and preclinical evidence regarding small-molecule inhibitors of the PD-1/PD-L1 immune checkpoint, considering features and responses related to the tumours and to the host immune system.
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http://dx.doi.org/10.1080/1061186X.2018.1440400DOI Listing
March 2019

Current Development Status of MEK Inhibitors.

Molecules 2017 Sep 26;22(10). Epub 2017 Sep 26.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300192, China.

The current development status of mitogen-activated protein kinase kinase (MEK) inhibitors, including the preclinical data and clinical study progress, has been summarized in this review. Different MEK inhibitors, possessing specific physicochemical properties and bioactivity characteristics, may provide different options for patients seeking treatment for cancer. Moreover, the combination of the MEK inhibitors with other therapies-such as chemotherapy, targeted therapy, and immunotherapy-may be a promising approach for clinical use.
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http://dx.doi.org/10.3390/molecules22101551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151813PMC
September 2017

Design, synthesis and biological evaluation of 1H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridine derivatives as c-Met inhibitors.

Bioorg Chem 2016 Apr 2;65:146-58. Epub 2016 Mar 2.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, #238 Baidi Road, Nankai District, Tianjin 300192, China. Electronic address:

Five novel 1H-pyrrolo[2,3-b]pyridine or 1H-pyrazolo[3,4-b]pyridine derivatives, with a methylene, sulfur, sulfoxide or cyclopropyl group as a linker, were designed, synthesized and biologically evaluated against c-Met and ALK. The development of these methods of compound synthesis may provide an important reference for the construction of novel 7-azaindole and 7-azaindazole derivatives with a single atom linker. The enzyme assay and cell assay in vitro showed that compound 9 displayed strong c-Met kinase inhibition with IC50 of 22.8nM, moderate ALK kinase inhibition, and strong cell inhibition with MKN-45 IC50 of 329nM and EBC-1 IC50 of 479nM. In order to find the better candidate compounds, compounds 8, 9 and 10 have been selected as tool compounds for further optimization.
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http://dx.doi.org/10.1016/j.bioorg.2016.02.009DOI Listing
April 2016

Discovery of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine inhibitors of Erk2.

Bioorg Med Chem Lett 2014 Jun 29;24(12):2635-9. Epub 2014 Apr 29.

Genentech Inc, 1 DNA Way, South San Francisco, CA 94080-4990, USA.

The discovery and optimization of a series of tetrahydropyridopyrimidine based extracellular signal-regulated kinase (Erks) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent and selective inhibition of Erk2 and knockdown of phospho-RSK levels in HepG2 cells and tumor xenografts.
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http://dx.doi.org/10.1016/j.bmcl.2014.04.068DOI Listing
June 2014

Influencing factors and sensitivity analysis of occupant impact injury in passenger compartment.

Traffic Inj Prev 2013 ;14(8):816-22

a Key Laboratory of Traffic Safety on Track, Ministry of Education , Central South University , Changsha , Hunan , China.

Objective: The study reported in this article addressed the influence of each factor (impact acceleration, table height h, table to seat distance l₁, interseat distance l₂, table contact stiffness k₁, seat contact stiffness k₂, etc.) on the extent of occupant impact injury in a railway vehicle secondary collision.

Methods: The vehicle's passenger compartment-occupant coupling model was established using proprietary software (MADYMO). The simulated occupant was MADYMO's validated Hybrid III 50th percentile dummy model, and the vehicle's passenger compartment model included the floor surface, side wall, seat (with cushion), backrest, and table. The floor surface and side wall were modeled as flat surfaces; the seat (with its cushion), backrest, and table were modeled as ellipsoids. Some 25 samples were selected for numerical simulation based on a 2-factor, 5-level, full-factorial experimental design: the response surface method (RSM) was applied to fit the mapping relationship between the occupant's injury parameters (head injury criterion [HIC] and thoracic cumulative 3-ms injury criterion [TC(3ms)]) and other multi-influence factors.

Results: Taking the seat-table structure model and seat-seat structure model as examples, the influence of each factor on the extent of the passenger compartment occupant's impact injury was assessed from the basis of traditional passenger compartment configurations found on Chinese trains. The sensitivity analysis of occupant injury parameters on these influence factors was carried out to determine the extent of the influence of each factor on each impact injury parameter.

Conclusions: The response surfaces of the occupant's injury parameters (HIC and TC(3ms)), and changes therein as the system's variables were altered showed that impact injury parameters and change thereto could be described intuitively and qualitatively. Some meaningful conclusions were obtained through the sensitivity analysis of occupant injury parameters to changes in these influence factors. The research offered a guideline for the design and manufacture of a train's passenger compartment structure.
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http://dx.doi.org/10.1080/15389588.2013.768341DOI Listing
January 2014

A safe and facile route to imidazole-1-sulfonyl azide as a diazotransfer reagent.

Org Lett 2013 Jan 14;15(1):18-21. Epub 2012 Dec 14.

State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300071, PR China.

A facile approach to the diazotransfer reagent of imidazole-1-sulfonyl azide was reported. The procedure was well optimized to clarify potential explosion risks. A high production yield as well as small batch variation was achieved even without careful pretreatment of reagents and solvents. HPLC and NMR methods to monitor the process were provided. These features made this protocol suitable for large scale preparation in academia and industry as well.
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http://dx.doi.org/10.1021/ol3028708DOI Listing
January 2013

Structure-activity relationships of SERMs optimized for uterine antagonism and ovarian safety.

Bioorg Med Chem Lett 2007 Jul 24;17(13):3544-9. Epub 2007 Apr 24.

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.

Structure-activity relationship studies are described, which led to the discovery of novel selective estrogen receptor modulators (SERMs) for the potential treatment of uterine fibroids. The SAR studies focused on limiting brain exposure and were guided by computational properties. Compounds with limited impact on the HPO axis were selected using serum estrogen levels as a biomarker for ovarian stimulation.
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http://dx.doi.org/10.1016/j.bmcl.2007.04.044DOI Listing
July 2007

A selective estrogen receptor modulator designed for the treatment of uterine leiomyoma with unique tissue specificity for uterus and ovaries in rats.

J Med Chem 2005 Nov;48(22):6772-5

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.

The design of a novel selective estrogen receptor modulator (SERM) for the potential treatment of uterine leiomyoma is described. 16 (LY2066948-HCl) binds with high affinity to estrogen receptors alpha and beta (ERalpha and ERbeta, respectively) and is a potent uterine antagonist with minimal effects on the ovaries as determined by serum biomarkers and histologic evaluation.
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http://dx.doi.org/10.1021/jm050723zDOI Listing
November 2005

Designing new chiral ketone catalysts. Asymmetric epoxidation of cis-olefins and terminal olefins.

J Org Chem 2002 Apr;67(8):2435-46

Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA.

This paper describes a new class of chiral oxazolidinone ketone catalyst for asymmetric epoxidation. High ee values have been obtained for a number of cyclic and acyclic cis-olefins. The epoxidation was stereospecific with no isomerization observed in the epoxidation of acyclic systems. Encouragingly high ee values have also been obtained for a number of terminal olefins. Mechanistic studies show that electronic interactions play an important role in stereodifferentiation.
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http://dx.doi.org/10.1021/jo010838kDOI Listing
April 2002

Asymmetric Strecker-Type Reaction of alpha-Aryl Ketones. Synthesis of (S)-alphaM4CPG, (S)-MPPG, (S)-AIDA, and (S)-APICA, the Antagonists of Metabotropic Glutamate Receptors.

J Org Chem 1999 Jan;64(1):120-125

State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, 354 Fenglin Lu, Shanghai 200032, China.

Heating a mixture of alpha-aryl ketone with (R)-phenylglycinol produces a mixture of imine and 1,3-dioxazolidine. Treatment of this mixture with trimethylsilyl cyanide followed by transformation of nitrile to ester gives Strecker-type reaction products. The diastereoselectivity of the generated alpha-amino esters is from 2/1 to 7/1, and the (R,S)isomer is found as the major product. The (R,S) and (R,R)isomers can be separated by conversion to their N-Cbz or cyclization derivatives. Using this methodology, four antagonists of metabotropic glutamate receptors, (S)-alphaM4CPG, (S)-MPPG, (S)-AIDA, and (S)-APICA, are synthesized.
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http://dx.doi.org/10.1021/jo981297aDOI Listing
January 1999
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