title: Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations.
abstract: Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.
authors.affiliation: La Jolla Laboratories, Pfizer Worldwide Research and Development , 10770 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Ted W
authors.initials: TW
authors.lastname: Johnson
authors.forename: Paul F
authors.initials: PF
authors.lastname: Richardson
authors.forename: Simon
authors.initials: S
authors.lastname: Bailey
authors.forename: Alexei
authors.initials: A
authors.lastname: Brooun
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Burke
authors.forename: Michael R
authors.initials: MR
authors.lastname: Collins
authors.forename: J Jean
authors.initials: JJ
authors.lastname: Cui
authors.forename: Judith G
authors.initials: JG
authors.lastname: Deal
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Deng
authors.forename: Dac
authors.initials: D
authors.lastname: Dinh
authors.forename: Lars D
authors.initials: LD
authors.lastname: Engstrom
authors.forename: Mingying
authors.initials: M
authors.lastname: He
authors.forename: Jacqui
authors.initials: J
authors.lastname: Hoffman
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hoffman
authors.forename: Qinhua
authors.initials: Q
authors.lastname: Huang
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kania
authors.forename: John C
authors.initials: JC
authors.lastname: Kath
authors.forename: Hieu
authors.initials: H
authors.lastname: Lam
authors.forename: Justine L
authors.initials: JL
authors.lastname: Lam
authors.forename: Phuong T
authors.initials: PT
authors.lastname: Le
authors.forename: Laura
authors.initials: L
authors.lastname: Lingardo
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Michele
authors.initials: M
authors.lastname: McTigue
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Palmer
authors.forename: Neal W
authors.initials: NW
authors.lastname: Sach
authors.forename: Tod
authors.initials: T
authors.lastname: Smeal
authors.forename: Graham L
authors.initials: GL
authors.lastname: Smith
authors.forename: Albert E
authors.initials: AE
authors.lastname: Stewart
authors.forename: Sergei
authors.initials: S
authors.lastname: Timofeevski
authors.forename: Huichun
authors.initials: H
authors.lastname: Zhu
authors.forename: Jinjiang
authors.initials: J
authors.lastname: Zhu
authors.forename: Helen Y
authors.initials: HY
authors.lastname: Zou
authors.forename: Martin P
authors.initials: MP
authors.lastname: Edwards
mesh_terms: D000631:Aminopyridines; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007769:Lactams; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D041681:NIH 3T3 Cells; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011720:Pyrazoles; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D007769:Lactams; D047029:Lactams, Macrocyclic; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; C000626173:ALK protein, human; C000626174:Alk protein, mouse; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; C000590786:lorlatinib