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

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.

Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives

“…A series of 1 H -indazole derivatives were synthesized using structure-guided drug design from lead compound 108 by Liu et al [ 64 ] and evaluated for their epidermal growth factor receptor (EGFR) kinase activity. The results indicated that compound 109 displayed strong potencies against EGFR T790M and EGFR kinases with IC 50 values of 5.3 and 8.3 nM, respectively ( Figure 20 ).…”

Allenamide as a bioisostere of acrylamide in the design and synthesis of targeted covalent inhibitors

“…In conclusion, the action of 14 on cell growth inhibition of NCI-H1975 cells is mediated by the inhibition of EGFR phosphorylation and the subsequent inactivation of two downstream signal pathways, namely, PI3K-AKT and RAF-MEK-ERK. 10,[27][28][29][30][31][32][33][34][35][36] In order to understand the biochemical reactivity profile of allenamide as a covalent warhead, we measured the pseudofirst-order reaction 9 rate constant of GSH addition to 14 or acrylamide containing marketed drugs 1-3 (Table 4). The rate constant, k pseudo 1st , observed for GSH addition to 14 is 302.5 × 10 −3 min −1 under our experimental conditions, which is about 7 to 28-fold higher than that of 1-3.…”

“…26 In view of the robust reactivity of allenamides towards thiol groups, we hypothesized that allenamide could be used as a bioisostere of the acrylamide moiety in small molecule drug design. In order to test this hypothesis, we replaced the acrylamide moiety of 2 with an allenamide group in an irreversible EGFR kinase inhibitor model system, 10,[27][28][29][30][31][32][33][34][35][36][37][38][39] which led to a series of novel TCIs.…”

Structural Perspective on Revealing and Altering Molecular Mechanisms of Genetic Variants Linked with Diseases

“…Pharmacophore models have also been used for identifying active molecules to mitigate the effects of mutations in many diseases [119][120][121][122] . For the cases where a sufficient number of active molecules are previously known for generating high-quality pharmacophore models, pharmacophore proves to be a powerful tool for drug 'lead' identification 116 .…”