2. Academic Validation
  3. 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

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

  • J Med Chem. 2014 Jun 12;57(11):4720-44. doi: 10.1021/jm500261q.
Ted W Johnson 1,  Paul F Richardson,  Simon Bailey,  Alexei Brooun,  Benjamin J Burke,  Michael R Collins,  J Jean Cui,  Judith G Deal,  Ya-Li Deng,  Dac Dinh,  Lars D Engstrom,  Mingying He,  Jacqui Hoffman,  Robert L Hoffman,  Qinhua Huang,  Robert S Kania,  John C Kath,  Hieu Lam,  Justine L Lam,  Phuong T Le,  Laura Lingardo,  Wei Liu,  Michele McTigue,  Cynthia L Palmer,  Neal W Sach,  Tod Smeal,  Graham L Smith,  Albert E Stewart,  Sergei Timofeevski,  Huichun Zhu,  Jinjiang Zhu,  Helen Y Zou,  Martin P Edwards
Affiliations

Affiliation

  • 1 La Jolla Laboratories, Pfizer Worldwide Research and Development , 10770 Science Center Drive, San Diego, California 92121, United States.
PMID: 24819116 DOI: 10.1021/jm500261q
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.

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