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.
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.
authors.forename: Simon
authors.identifier: 0000-0001-8901-8992
authors.initials: S
authors.lastname: Planken
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Behenna
authors.forename: Sajiv K
authors.initials: SK
authors.lastname: Nair
authors.forename: Theodore O
authors.initials: TO
authors.lastname: Johnson
authors.forename: Asako
authors.initials: A
authors.lastname: Nagata
authors.forename: Chau
authors.initials: C
authors.lastname: Almaden
authors.forename: Simon
authors.initials: S
authors.lastname: Bailey
authors.forename: T Eric
authors.initials: TE
authors.lastname: Ballard
authors.forename: Louise
authors.initials: L
authors.lastname: Bernier
authors.forename: Hengmiao
authors.initials: H
authors.lastname: Cheng
authors.forename: Sujin
authors.initials: S
authors.lastname: Cho-Schultz
authors.forename: Deepak
authors.initials: D
authors.lastname: Dalvie
authors.forename: Judith G
authors.initials: JG
authors.lastname: Deal
authors.forename: Dac M
authors.initials: DM
authors.lastname: Dinh
authors.forename: Martin P
authors.initials: MP
authors.lastname: Edwards
authors.forename: Rose Ann
authors.initials: RA
authors.lastname: Ferre
authors.forename: Ketan S
authors.initials: KS
authors.lastname: Gajiwala
authors.forename: Michelle
authors.initials: M
authors.lastname: Hemkens
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kania
authors.forename: John C
authors.initials: JC
authors.lastname: Kath
authors.forename: Jean
authors.initials: J
authors.lastname: Matthews
authors.forename: Brion W
authors.initials: BW
authors.lastname: Murray
authors.forename: Sherry
authors.initials: S
authors.lastname: Niessen
authors.forename: Suvi T M
authors.initials: ST
authors.lastname: Orr
authors.forename: Mason
authors.initials: M
authors.lastname: Pairish
authors.forename: Neal W
authors.initials: NW
authors.lastname: Sach
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.forename: Manli
authors.initials: M
authors.lastname: Shi
authors.forename: James
authors.initials: J
authors.lastname: Solowiej
authors.forename: Khanh
authors.initials: K
authors.lastname: Tran
authors.forename: Elaine
authors.initials: E
authors.lastname: Tseng
authors.forename: Paolo
authors.initials: P
authors.lastname: Vicini
authors.forename: Yuli
authors.initials: Y
authors.lastname: Wang
authors.forename: Scott L
authors.initials: SL
authors.lastname: Weinrich
authors.forename: Ru
authors.initials: R
authors.lastname: Zhou
authors.forename: Michael
authors.initials: M
authors.lastname: Zientek
authors.affiliation: Wuxi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Longqing
authors.initials: L
authors.lastname: Liu
authors.affiliation: Wuxi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Yiqin
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Wuxi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Shuibo
authors.initials: S
authors.lastname: Xin
authors.affiliation: Wuxi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Chengyi
authors.initials: C
authors.lastname: Zhang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lafontaine
mesh_terms: D000178:Acrylamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D004285:Dogs; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D054879:Halogenation; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011759:Pyrrolidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats
chemical_list: D000178:Acrylamides; D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines; C512478:EGFR protein, human; D066246:ErbB Receptors