1. Academic Validation
  2. Discovery of 1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one (PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants

Discovery of 1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one (PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants

  • J Med Chem. 2016 Mar 10;59(5):2005-24. doi: 10.1021/acs.jmedchem.5b01633.
Hengmiao Cheng 1 Sajiv K Nair 1 Brion W Murray 1 Chau Almaden 1 Simon Bailey 1 Sangita Baxi 1 Doug Behenna 1 Sujin Cho-Schultz 1 Deepak Dalvie 1 Dac M Dinh 1 Martin P Edwards 1 Jun Li Feng 1 Rose Ann Ferre 1 Ketan S Gajiwala 1 Michelle D Hemkens 1 Amy Jackson-Fisher 1 Mehran Jalaie 1 Ted O Johnson 1 Robert S Kania 1 Susan Kephart 1 Jennifer Lafontaine 1 Beth Lunney 1 Kevin K-C Liu 1 Zhengyu Liu 1 Jean Matthews 1 Asako Nagata 1 Sherry Niessen 1 Martha A Ornelas 1 Suvi T M Orr 1 Mason Pairish 1 Simon Planken 1 Shijian Ren 2 Daniel Richter 1 Kevin Ryan 1 Neal Sach 1 Hong Shen 1 Tod Smeal 1 Jim Solowiej 1 Scott Sutton 1 Khanh Tran 1 Elaine Tseng 1 William Vernier 1 Marlena Walls 1 Shuiwang Wang 2 Scott L Weinrich 1 Shuibo Xin 2 Haiwei Xu 2 Min-Jean Yin 1 Michael Zientek 1 Ru Zhou 1 John C Kath 1
Affiliations

Affiliations

  • 1 La Jolla Laboratories, Pfizer Worldwide Research and Development , 10770 Science Center Drive, San Diego, California 92121, United States.
  • 2 Wuxi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-19985
    98.87%, EGFR抑制剂