RRC ID 65037
Author Planken S, Behenna DC, Nair SK, Johnson TO, Nagata A, Almaden C, Bailey S, Ballard TE, Bernier L, Cheng H, Cho-Schultz S, Dalvie D, Deal JG, Dinh DM, Edwards MP, Ferre RA, Gajiwala KS, Hemkens M, Kania RS, Kath JC, Matthews J, Murray BW, Niessen S, Orr ST, Pairish M, Sach NW, Shen H, Shi M, Solowiej J, Tran K, Tseng E, Vicini P, Wang Y, Weinrich SL, Zhou R, Zientek M, Liu L, Luo Y, Xin S, Zhang C, Lafontaine J.
Title Discovery of N-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR.
Journal J Med Chem
Abstract Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of PF-06459988 (1), an irreversible pyrrolopyrimidine inhibitor of EGFR T790M mutants, was recently disclosed.1 Herein, we describe our continued efforts to achieve potency across EGFR oncogenic mutations and improved kinome selectivity, resulting in the discovery of clinical candidate PF-06747775 (21), which provides potent EGFR activity against the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties. Compound 21 is currently being evaluated in phase-I clinical trials of mutant EGFR driven NSCLC.
Volume 60(7)
Pages 3002-3019
Published 2017-4-13
DOI 10.1021/acs.jmedchem.6b01894
PMID 28287730
MeSH Acrylamides / chemistry Acrylamides / pharmacokinetics Acrylamides / pharmacology Animals Carcinoma, Non-Small-Cell Lung / drug therapy Carcinoma, Non-Small-Cell Lung / genetics Cell Line, Tumor Dogs Drug Design* ErbB Receptors / antagonists & inhibitors* ErbB Receptors / genetics* Halogenation Humans Lung / drug effects Lung / metabolism Lung Neoplasms / drug therapy Lung Neoplasms / genetics Mice Models, Molecular Molecular Docking Simulation Mutation Protein Kinase Inhibitors / chemistry* Protein Kinase Inhibitors / pharmacokinetics Protein Kinase Inhibitors / pharmacology* Pyrrolidines / chemistry* Pyrrolidines / pharmacokinetics Pyrrolidines / pharmacology* Rats
IF 6.205
Human and Animal Cells PC-9(RCB4455)