CHMFL-EGFR-202

Description

CHMFL-EGFR-202 is a potent, irreversible inhibitor of epidermal growth factor receptor (EGFR) mutant kinase, with IC50s of 5.3 nM and 8.3 nM for drug-resistant mutant EGFR T790M and WT EGFR kinases, respectively. CHMFL-EGFR-202 exhibits ∼10-fold selectivity for EGFR L858R/T790M against the EGFR wild-type in cells. CHMFL-EGFR-202 adopts a covalent "DFG-in-C-helix-out" inactive binding conformation with EGFR, with strong antiproliferative effects against EGFR mutant-driven nonsmall-cell lung cancer (NSCLC) cell lines[1]. EGFRT790M|5.3 nM (IC50)|EGFR|8.3 nM (IC50)|ErbB2|8.1 nM (IC50)|ErbB4|3.2 nM (IC50)|MEK1|161 nM (IC50)|Btk|24.5 nM (IC50)|BLK|8.1 nM (IC50)|BMX|111 nM (IC50)

CHMFL-EGFR-202 potently inhibits EGFR primary mutants (L858R, del19) and drug-resistant mutant L858R/T790M[1].CHMFL-EGFR-202 displays strong binding affinities against wild-type, G719C/S, L858R, L858R/T790M, L861Q, and T790M among EGFR wild-type and mutant kinases[1].CHMFL-EGFR-202 also exhibits strong binding affinities against BLK, BMX, BTK, ERBB2, ERBB4, LOK, MEK1, and MEK5 kinases (percent of control score less than 1% at 1 μM)[1].CHMFL-EGFR-202 trongly inhibits BLK, BTK, ERBB2 and ERBB4 with IC50s of 8.1 nM, 24.5 nM, 8.1 nM and 3.2 nM, respectively[1].CHMFL-EGFR-202 moderately inhibits BMX and MEK1 kinases with IC50 of 111.0 nM and 161.0 nM[1].

Uses

CHMFL-EGFR-202 is a potent, irreversible inhibitor of epidermal growth factor receptor (EGFR) mutant kinase, with IC50s of 5.3 nM and 8.3 nM for drug-resistant mutant EGFR T790M and WT EGFR kinases, respectively. CHMFL-EGFR-202 exhibits ～10-fold selectivity for EGFR L858R/T790M against the EGFR wild-type in cells. CHMFL-EGFR-202 adopts a covalent “DFG-in-C-helix-out” inactive binding conformation with EGFR, with strong antiproliferative effects against EGFR mutant-driven nonsmall-cell lung cancer (NSCLC) cell lines[1].

IC 50

EGFR^T790M: 5.3 nM (IC₅₀); EGFR: 8.3 nM (IC₅₀); ErbB2: 8.1 nM (IC₅₀); ErbB4: 3.2 nM (IC₅₀); MEK1: 161 nM (IC₅₀); Btk: 24.5 nM (IC₅₀); BLK: 8.1 nM (IC₅₀); BMX: 111 nM (IC₅₀)

References

[1]. Wang A, et al. 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.