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Discovery of (R)-1-(3-(4-Amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (CHMFL-EGFR-202) as a Novel Irreversible EGFR Mutant Kinase Inhibitor with a Distinct Binding Mode.

Wang A, Li X, Wu H, Zou F, Yan XE, Chen C, Hu C, Yu K, Wang W, Zhao P, Wu J, Qi Z, Wang W, Wang B, Wang L, Ren T, Zhang S, Yun CH, Liu J, Liu Q
J Med Chem 60 2944-2962 (2017)
Cited: 15 times
EuropePMC logo PMID: 28282122

Abstract

On the basis of Ibrutinib's core pharmacophore, which was moderately active to EGFR T790M mutant, we discovered novel epidermal growth factor receptor (EGFR) inhibitor compound 19 (CHMFL-EGFR-202), which potently inhibited EGFR primary mutants (L858R, del19) and drug-resistant mutant L858R/T790M. Compound 19 displayed a good selectivity profile among 468 kinases/mutants tested in the KINOMEscan assay (S score (1) = 0.02). In particular, it did not exhibit apparent activities against INSR and IGF1R kinases. The X-ray crystal structure revealed that this class of inhibitors formed a covalent bond with Cys797 in a distinct "DFG-in-C-helix-out" inactive EGFR conformation. Compound 19 displayed strong antiproliferative effects against EGFR mutant-driven nonsmall cell lung cancer (NSCLC) cell lines such as H1975, PC9, HCC827, and H3255 but not the wild-type EGFR expressing cells. In the H1975 and PC9 cell-inoculated xenograft mouse models, compound 19 exhibited dose-dependent tumor growth suppression efficacy without obvious toxicity. Compound 19 might be a potential drug candidate for EGFR mutant-driven NSCLC.

Reviews - 5gnk mentioned but not cited (2)

  1. Toward structure-based drug design against the epidermal growth factor receptor (EGFR). Haddad Y, Remes M, Adam V, Heger Z. Drug Discov Today 26 289-295 (2021)
  2. 4-Aminopyrazolopyrimidine scaffold and its deformation in the design of tyrosine and serine/threonine kinase inhibitors in medicinal chemistry. Chen X, Huang Y, Xu W, Cai Y, Yang Y. RSC Med Chem 13 1008-1028 (2022)

Articles - 5gnk mentioned but not cited (8)

  1. Spatiotemporal identification of druggable binding sites using deep learning. Kozlovskii I, Popov P. Commun Biol 3 618 (2020)
  2. Leveraging Atropisomerism to Obtain a Selective Inhibitor of RET Kinase with Secondary Activities toward EGFR Mutants. Toenjes ST, Garcia V, Maddox SM, Dawson GA, Ortiz MA, Piedrafita FJ, Gustafson JL. ACS Chem Biol 14 1930-1939 (2019)
  3. Multiple targeted self-emulsifying compound RGO reveals obvious anti-tumor potential in hepatocellular carcinoma. He S, Tian S, He X, Le X, Ning Y, Chen J, Chen H, Mu J, Xu K, Xiang Q, Wu Y, Chen J, Xiang T. Mol Ther Oncolytics 22 604-616 (2021)
  4. EMBER-Embedding Multiple Molecular Fingerprints for Virtual Screening. Mendolia I, Contino S, De Simone G, Perricone U, Pirrone R. Int J Mol Sci 23 2156 (2022)
  5. Systematic characterization of the components and molecular mechanisms of Jinshui Huanxian granules using UPLC-Orbitrap Fusion MS integrated with network pharmacology. Yuan J, Zhao D, Liu XF, Tian YG, Zhang HJ, Feng SX, Li JS. Sci Rep 12 12476 (2022)
  6. Case Reports A Lung Cancer Patient Harboring a Rare Oncogenic EGFR Exon 20 V786M Mutation Responded to a Third-Generation Tyrosine Kinase Inhibitor: Case Report and Review of the Literature. Zhu Q, Jiang M, Li W, Sun S, Li J, Stebbing J, Liang X, Peng L. Front Oncol 12 912426 (2022)
  7. Network Pharmacology and Bioinformatics Methods Reveal the Mechanism of Berberine in the Treatment of Ischaemic Stroke. Song K, Sun Y, Liu H, Li Y, An N, Wang L, Zhang H, Yang F, Xing Y, Gao Y. Evid Based Complement Alternat Med 2022 5160329 (2022)
  8. Potential Mechanisms of Shu Gan Jie Yu Capsule in the Treatment of Mild to Moderate Depression Based on Systemic Pharmacology and Current Evidence. Li T, Qiu T, Zeng Y, Kang B, Tang X, Yang N, Xiao H. Evid Based Complement Alternat Med 2022 3321099 (2022)


Reviews citing this publication (2)

  1. Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives. Zhang SG, Liang CG, Zhang WH. Molecules 23 E2783 (2018)
  2. Structural Perspective on Revealing and Altering Molecular Functions of Genetic Variants Linked with Diseases. Peng Y, Alexov E, Basu S. Int J Mol Sci 20 E548 (2019)

Articles citing this publication (3)

  1. Allenamide as a bioisostere of acrylamide in the design and synthesis of targeted covalent inhibitors. Chen D, Guo D, Yan Z, Zhao Y. Medchemcomm 9 244-253 (2018)
  2. Design, synthesis and biological evaluation of 4-bromo-N-(3,5-dimethoxyphenyl)benzamide derivatives as novel FGFR1 inhibitors for treatment of non-small cell lung cancer. Xie Z, Cheng D, Luo L, Shen G, Pan S, Pan Y, Chen B, Wang X, Liu Z, Zhang Y, Ye F. J Enzyme Inhib Med Chem 33 905-919 (2018)
  3. Discovery and characterization of a novel highly potent and selective type II native and drug-resistant V299L mutant BCR-ABL inhibitor (CHMFL-ABL-039) for Chronic Myeloid Leukemia (CML). Wu J, Wang A, Li X, Chen C, Qi Z, Hu C, Wang W, Wu H, Huang T, Zhao M, Wang W, Hu Z, Liu Q, Wang B, Wang L, Li L, Ge J, Ren T, Xia R, Liu J, Liu Q. Cancer Biol Ther 20 877-885 (2019)


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