Journal of Medicinal Chemistry p. 2005 - 2024 (2016)
Update date:2022-08-15
Topics:
Cheng, Hengmiao
Nair, Sajiv K.
Murray, Brion W.
Almaden, Chau
Bailey, Simon
Baxi, Sangita
Behenna, Doug
Cho-Schultz, Sujin
Dalvie, Deepak
Dinh, Dac M.
Edwards, Martin P.
Feng, Jun Li
Ferre, Rose Ann
Gajiwala, Ketan S.
Hemkens, Michelle D.
Jackson-Fisher, Amy
Jalaie, Mehran
Johnson, Ted O.
Kania, Robert S.
Kephart, Susan
Lafontaine, Jennifer
Lunney, Beth
Liu, Kevin K.-C.
Liu, Zhengyu
Matthews, Jean
Nagata, Asako
Niessen, Sherry
Ornelas, Martha A.
Orr, Suvi T. M.
Pairish, Mason
Planken, Simon
Ren, Shijian
Richter, Daniel
Ryan, Kevin
Sach, Neal
Shen, Hong
Smeal, Tod
Solowiej, Jim
Sutton, Scott
Tran, Khanh
Tseng, Elaine
Vernier, William
Walls, Marlena
Wang, Shuiwang
Weinrich, Scott L.
Xin, Shuibo
Xu, Haiwei
Yin, Min-Jean
Zientek, Michael
Zhou, Ru
Kath, John C.
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.
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