5hg9

Publication Abstract from PubMed

First generation EGFR TKIs (gefitinib, erlotinib) provide significant clinical benefit for NSCLC cancer patients with oncogenic EGFR mutations. Ultimately, these patients disease progresses, often driven by a second-site mutation in the EGFR kinase domain (T790M). Another liability of the first generation drugs is severe adverse events driven by inhibition of WT EGFR. As such, our goal was to develop a highly potent irreversible inhibitor with the largest selectivity ratio between the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT EGFR. A unique approach to develop covalent inhibitors, optimization of reversible binding affinity, served as a cornerstone of this effort. PF-06459988, was discovered as a novel, third generation irreversible inhibitor, which demonstrates (i) high potency and specificity to the T790M-containing double mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic warhead, (iii) greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors and (iv) minimal activity against WT EGFR.

Discovery of 1-{(3R,4R)-3-[5-Chloro-2-(1-methyl-1H-pyrazol-4-ylamino)-7H-pyrrolo[2,3-d]pyrimid in-4-yloxymethyl]-4-methoxy-pyrrolidin-1-yl}propenone (PF-06459988), A Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants.,Cheng H, Nair SK, Murray BW, Almaden C, Bailey S, Baxi S, Behenna DC, Cho-Schultz S, Dalvie D, Dinh DM, Edwards MP, Feng JL, Ferre R, Gajiwala KS, Hemkens MD, Jackson-Fisher A, Jalaie M, Johnson TO, Kania RS, Kephart S, Lafontaine JA, Lunney E, Liu KK, Liu Z, Matthews J, Nagata A, Niessen S, Ornelas MA, Orr ST, Pairish M, Planken S, Ren S, Richter DT, Ryan K, Sach NW, Shen H, Smeal T, Solowiej J, Sutton SC, Tran K, Tseng E, Vernier WF, Walls M, Wang S, Weinrich SL, Xin S, Xu H, Yin MJ, Zhou R, Zientek M, Kath J J Med Chem. 2016 Jan 12. PMID:26756222^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.