Article
Biochemistry & Molecular Biology
Ru Dong, Xin Zhou, Min Wang, Wen Li, Jin-Yang Zhang, Xin Zheng, Kai-Xiang Tang, Li-Ping Sun
Summary: DDR1, a receptor tyrosine kinase that plays a role in tumor growth, metastasis development, and tumor dormancy, has become an attractive target for anticancer therapy. Compound 6c, a potential DDR1 inhibitor, is able to suppress DDR1 kinase activity and inhibit cell proliferation effectively.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Ho Shin Kim, Diana Ortiz, Tara Man Kadayat, Corinne M. Fargo, Jared T. Hammill, Yizhe Chen, Amy L. Rice, Kristin L. Begley, Gaurav Shoeran, William Pistel, Phillip A. Yates, Marco A. Sanchez, Scott M. Landfear, R. Kiplin Guy
Summary: Leishmaniasis is a neglected tropical disease with limited treatment options. The discovery of 2,4,5-trisubstituted benzamides as potent antileishmanial compounds with low aqueous solubility has opened up new possibilities for drug development. Through extensive studies on structure-activity and structure-property relationships, early leads with suitable potency, stability, and solubility were identified. One of the early leads, compound 79, showed high oral bioavailability and effectively inhibited Leishmania growth in animal models. These benzamide compounds hold promising potential for the development of orally available antileishmanial drugs.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Tingting Jin, Lei Xu, Peipei Wang, Xiaobei Hu, Runyuan Zhang, Zhiqi Wu, Wenxin Du, Weijuan Kan, Kun Li, Chang Wang, Yubo Zhou, Jia Li, Tao Liu
Summary: In this study, a strategy involving trifluoromethyl substitution was used to develop an orally bioavailable CHK1 inhibitor, compound 6c, which exhibited higher plasma exposure and good kinase selectivity in mice. Compound 6c demonstrated significant antiproliferative effects in various cell lines and inhibited tumor growth in mouse models. Additionally, it showed a synergistic effect when combined with gemcitabine in certain xenograft mouse models.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Minhao Huang, Yongjun Huang, Jing Guo, Lei Yu, Yu Chang, Xiaolu Wang, Jinfeng Luo, Yanhui Huang, Zhengchao Tu, Xiaoyun Lu, Yong Xu, Zhimin Zhang, Zhang Zhang, Ke Ding
Summary: A series of pyrido [2, 3-d]pyrimidin-7(8H)-ones were synthesized as new selective orally bioavailable Threonine Tyrosine Kinase (TTK) inhibitors. Compound 5o demonstrated potent binding affinity and antitumor activity, good oral pharmacokinetic properties, and promising efficacy in combination therapy with paclitaxel in animal models.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Sangmi Oh, M. Daben J. Libardo, Shaik Azeeza, Gary T. Pauly, Jose Santinni O. Roma, Andaleeb Sajid, Yoshitaka Tateishi, Caroline Duncombe, Michael Goodwin, Thomas R. Ioerger, Paul G. Wyatt, Peter C. Ray, David W. Gray, Helena I. M. Boshoff, Clifton E. Barry
Summary: Pyrazolo[1,5-a]pyrimidin-7(4H)-one was identified as a potential antituberculosis lead through high-throughput whole-cell screening. The synthesized analogues showed substantial improvements in antitubercular activity with low cytotoxicity, and promising activity against Mtb. Resistance to these compounds was found to be due to mutation of a specific hydroxylase.
ACS INFECTIOUS DISEASES
(2021)
Article
Chemistry, Multidisciplinary
Badr Jismy, Gerald Guillaumet, Mohamed Akssira, Abdellatif Tikad, Mohamed Abarbri
Summary: A convenient and efficient synthetic route to C3-arylated 7-trifluoromethylpyrazolo[1,5-a]pyrimidin-5-one derivatives has been developed via Suzuki-Miyaura cross-coupling reaction. The method enables the synthesis of a variety of arylated compounds with potential anti-inflammatory properties and neurodegenerative disorder targeting abilities.
Article
Biochemistry & Molecular Biology
Ziva Zajec, Jaka Dernovsek, Martin Distel, Martina Gobec, Tihomir Tomasic
Summary: In this article, a new class of allosteric Hsp90 C-terminal domain (CTD) inhibitors based on the virtual screening hit TVS24 is reported, which showed anti-proliferative activity in the SK-N-MC Ewing sarcoma cell line. The optimized compounds exhibited enhanced anticancer activity in the SK-N-MC cell line. Exposure to the most potent analogue 11c depleted critical Hsp90 client proteins involved in cancer pathways without inducing a heat shock response. This study highlights Hsp90 CTD inhibitors as promising new agents for the treatment of Ewing sarcoma.
BIOORGANIC CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Xiandeng Li, Tao Yang, Mengshi Hu, Yingxue Yang, Minghai Tang, Dexin Deng, Kongjun Liu, Suhong Fu, Yan Tan, Huan Wang, Yong Chen, Chufeng Zhang, Yong Guo, Bin Peng, Wenting Si, Zhuang Yang, Lijuan Chen
Summary: In this study, a series of novel compounds were synthesized that exhibited inhibitory effects on FLT3 and CDK4 kinases. The optimized compound 23k showed low nanomolar range activities and demonstrated antitumor therapeutic effects in both in vitro and in vivo evaluations.
BIOORGANIC CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Wei-Ting Chang, Sheng-Nan Wu
Summary: The novel compound QO-40 is a selective activator of KCNQ2/KCNQ3 K+ channels, and has been found to stimulate Ca2+-activated K+ current in pituitary GH(3) lactotrophs. QO-40 directly interacts with BKCa channels, increasing the amplitude of I-K(Ca) in these cells by altering channel activation curve and gating charge, as well as increasing channel hysteresis.
Article
Pharmacology & Pharmacy
Qi Wang, Bixi Tang, Dandan Sun, Ying Dong, Yinchun Ji, Huanyu Shi, Liwei Zhou, Yueyue Yang, Menglan Luo, Qian Tan, Lin Chen, Yue Dong, Cong Li, Rongrong Xie, Yi Zang, Jingkang Shen, Bing Xiong, Jia Li, Danqi Chen
Summary: Idiopathic pulmonary fibrosis (IPF) is a serious chronic lung disease with inaccurate diagnosis, limited clinical therapy, and high mortality. The discoidin domain receptors (DDR) have been identified as promising drug targets for IPF treatment, and compound 47 shows potential as a candidate for further drug development.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Chemistry, Inorganic & Nuclear
Felipe S. Stefanello, Yuri G. Kappenberg, Juliane N. Araujo, Steffany Z. Franceschini, Nilo Zanatta, Bernardo A. Iglesias, Helio G. Bonacorso, Marcos A. P. Martins
Summary: This paper describes an efficient approach to synthesize a novel trifluoromethylated heterocyclic system using aryldiazenyl as starting materials. The [3 + 3] cyclocondensation reaction between (E)-4-(aryldiazenyl)-1H-pyrazol-3,5-diamines and selected 4-alkoxy-4-(alkyl/aryl/heteroaryl)-1,1,1-trifluoroalk-3-en-2-ones was performed under reflux conditions in acetonitrile and sodium acetate, resulting in 50-90% yields. The synthesized compounds were characterized by NMR and SC-XRD techniques, and their electronic properties were investigated, revealing potential applications in the future.
JOURNAL OF FLUORINE CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Yanle Zhi, Hongmei Li, Pei Yang, Qiaomei Jin, Chao Yao, Baoquan Li, Jun Ling, Hao Guo, Tonghui Li, Jianlin Jin, Yue Wang, Yadong Chen, Tao Lu, Shuai Lu
Summary: In recent years, FLT3 has been identified as an exciting target for AML treatment. However, resistance to FLT3 inhibitors caused by acquired point mutations in the tyrosine kinase domain (TKD) has limited their efficacy. Compound LT-540-717 (32) has been discovered as a potent FLT3 inhibitor with inhibitory activity against multiple acquired FLT3 mutations. It also exhibits antiproliferative activity against FLT3-mutation driven cells and shows potential as a new anti-AML drug.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Hamish S. Sutherland, Peter J. Choi, Guo-Liang Lu, Anna C. Giddens, Amy S. T. Tong, Scott G. Franzblau, Christopher B. Cooper, Brian D. Palmer, William A. Denny
Summary: In this study, a series of novel pyrazolo[1,5-a]pyrimidin-7-amine compounds were designed, synthesized and subjected to comprehensive structure-activity relationship studies. Some of these compounds showed potent activity in inhibiting the growth of M.tb, low toxicity and good stability, highlighting their potential as inhibitors of M.tb.
Article
Chemistry, Medicinal
Shuai Wang, Sai-Qi Wang, Qiu-Xu Teng, Zi-Ning Lei, Zhe-Sheng Chen, Xiao-Bing Chen, Hong-Min Liu, Bin Yu
Summary: The triazolo[1,5-a]pyrimidine derivative WS-898 was discovered as a highly effective ABCB1 inhibitor capable of reversing PTX resistance in cells. WS-898 inhibited the efflux function of ABCB1, leading to increased intracellular PTX concentration and enhanced drug efficacy. Additionally, WS-898 showed promising results in in vivo PTX sensitization without causing obvious toxicity.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Felipe S. Stefanello, Yuri G. Kappenberg, Juliane N. Araujo, Bianca Dozza, Pablo A. Nogara, Joao B. T. Rocha, Nilo Zannata, Marcos A. P. Martins, Helio G. Bonacorso, Bernardo A. Iglesias
Summary: The convenient synthesis of a series of alkyne-spacer derivatives from the Sonogashira cross-coupling reaction on diazenyl-pyrazolo[1,5-a]pyrimidin-2-amine compounds, along with their optical properties, redox analysis, and interaction with HSA biomacromolecules, suggests their potential as optical sensors for albumins.
Article
Chemistry, Medicinal
Xiaoyun Lu, Jeff B. Smaill, Ke Ding
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Chemistry, Multidisciplinary
Nan Ma, Jun Hu, Zhi-Min Zhang, Wenyan Liu, Minhao Huang, Youlong Fan, Xingfeng Yin, Jigang Wang, Ke Ding, Wencai Ye, Zhengqiu Li
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2020)
Article
Pharmacology & Pharmacy
Liang Jiang, Yuting Wang, Qian Li, Zhengchao Tu, Sihua Zhu, Sanfang Tu, Zhang Zhang, Ke Ding, Xiaoyun Lu
Summary: A new class of selective Bcr-Abl(T315I) proteolysis-targeting chimeric degraders were designed, synthesized, and evaluated, with 7o exhibiting the most potent degradation efficacy and significant tumor regression in cell and animal models.
ACTA PHARMACEUTICA SINICA B
(2021)
Editorial Material
Chemistry, Medicinal
Craig W. Lindsley, James Barrow, Kelly Chibale, Maria Laura Bolognesi, Stuart Conway, William Denny, Ke Ding, Stefan Laufer, Luhua Lai, Hong Liu, Nouri Neamati, Takayoshi Suzuki, Nicholas Meanwell, Wendy Young
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Oncology
Kaili Jiang, Xia Tang, Jing Guo, Rui He, Shingpan Chan, Xiaojuan Song, Zhengchao Tu, Yuting Wang, Xiaomei Ren, Ke Ding, Zhang Zhang
Summary: GZD824, a third generation ABL inhibitor, has been shown to overcome FGFR1-V561F/M mutant resistance in vitro and in vivo, suggesting its potential efficacy for treating patients with FGFR1 abnormal activation or mutant resistance in clinical trials.
Article
Chemistry, Medicinal
Xiaoyun Lu, Jeff B. Smaill, Adam Patterson, Ke Ding
Summary: Small molecule covalent kinase inhibitors (CKIs) have advantages for sustained target inhibition and high selectivity, with major medicinal chemistry strategies involving the addition of a warhead to a reversible lead/inhibitor scaffold to generate CKIs, while also facing challenges in drug discovery in this area.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Zhen Zhang, Jie Li, Hao Chen, Jing Huang, Xiaojuan Song, Zheng-Chao Tu, Zhang Zhang, Lijie Peng, Yang Zhou, Ke Ding
Summary: Aberrant FGF19/FGFR4 signaling has been identified as an oncogenic driver for human hepatocellular carcinoma (HCC). A new series of inhibitors targeting FGFR4 have been synthesized, and the representative compound 9ka showed potent activity against FGFR4 with excellent kinome selectivity. Compound 9ka also demonstrated favorable pharmacokinetic properties and induced significant tumor regression in a mouse model without apparent toxicity. Compound 9ka may serve as a promising lead compound for further development of anticancer drugs.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Jibu Lu, Yongjun Huang, Jing Huang, Rui He, Minhao Huang, Xiaoyun Lu, Yong Xu, Fengtao Zhou, Zhang Zhang, Ke Ding
Summary: The first examples of threonine tyrosine kinase (TTK) PROTACs were successfully designed and synthesized, showing strong degradation effects in human colorectal cancer cells and potential anticancer activities.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Zhen Wang, Weixue Huang, Kaijie Zhou, Xiaomei Ren, Ke Ding
Summary: Protein kinases have been proven to be effective targets for cancer drug discovery, but most drugs inhibit kinase catalytic activity by binding to ATP-site. Recent studies have shown that kinases also have noncatalytic functions, which play important roles in cellular signaling and cell fate controls. Small-molecule modulators targeting the noncatalytic functions of kinases have emerged as promising therapeutic strategies. This article summarizes the noncatalytic functions of kinases and discusses the progress in developing small-molecule modulators. It is speculated that targeting the noncatalytic functions could open a new direction for kinase-based drug discovery.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Peng Lyu, Kaili Jiang, Yuee Zhou, Jun Hu, Yu Chang, Zhang Zhang, Minhao Huang, Zhi-Min Zhang, Ke Ding, Piliang Hao, Ligen Lin, Zhengqiu Li
Summary: This study successfully identified the cellular off-target NT5DC1 of HP-1, a potential drug candidate for non-small cell lung cancer, through chemical proteomics and bioimaging studies.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Zuqin Wang, Jie Wang, Yongjin Wang, Shuang Xiang, Xiaojuan Song, Zhengchao Tu, Yang Zhou, Zhi-Min Zhang, Zhang Zhang, Ke Ding, Xiaoyun Lu
Summary: In this study, a novel TRK inhibitor 7b was reported. It is a highly selective macrocycle-based potent type II inhibitor that exhibits high inhibitory activity against TRK fusion proteins and wild type. Additionally, 7b showed potent antiproliferative activity against various mutants and displayed extraordinary selectivity for phosphorylation.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Yue Liu, Jiacong Liu, Xianfang Zhang, Cuiping Guo, Zhi-Min Zhang, Xiwen Xing, Ke Ding, Zhengqiu Li
Summary: Chemical proteomics is a powerful technology for studying uncharacterized proteins in the human proteome. A new protein-labeling strategy using nitrile oxide has been developed, which can efficiently react with target proteins. This method has shown excellent chemoselectivity and successfully characterized over 4000 cysteine residues, including KRAS G12C, demonstrating its complementary utility.
ACS CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Medicinal
Yiying Wei, Xinxin Xu, Minchuan Jiang, Yongxing Wang, Yang Zhou, Zhen Wang, Zhang Zhang, Fengtao Zhou, Ke Ding
Summary: A new selective GSPT1 degrader was developed, which could effectively degrade GSPT1 and showed good selectivity in the global proteomic profiling study. The compound also displayed good antiproliferative activities and induced cell cycle arrest and apoptosis in U937 cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Shumin Lv, Fang Xu, Youlong Fan, Ke Ding, Zhengqiu Li
Summary: Due to the limited targets for drug development, triple-negative breast cancer (TNBC) is considered a challenging disease for chemotherapy. In this study, a set of novel electrophilic warheads was used to search for potential targets for TNBC in chemical proteomics studies. These warheads were found to modify not only highly nucleophilic residues but also weakly nucleophilic residues. Cys12 of Kirsten rat sarcoma (KRASG12C) was successfully labeled by cyclopropenone and cyclopropeniminium ions. Preliminary results showed moderate inhibitory activity against TNBC cells with these electrophile-based probes, and FABP5 was identified as a potential target for TNBC through further functional validation experiments.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Zuqin Wang, Jie Wang, Yongjin Wang, Shuang Xiang, Hengliang Zhou, Shukai Song, Xiaojuan Song, Zhengchao Tu, Yang Zhou, Ke Ding, Zhi-Min Zhang, Zhang Zhang, Xiaoyun Lu
Summary: This study focuses on the development of new type II TRK inhibitors to combat acquired resistance mutations. Compound 10g displayed excellent potency against TRK mutants and demonstrated strong inhibition of cell proliferation. The results provide a promising lead compound for pan-anticancer drug discovery.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)