2. Academic Validation
  3. Discovery of Clinical Candidate CEP-37440, a Selective Inhibitor of Focal Adhesion Kinase (FAK) and Anaplastic Lymphoma Kinase (ALK)

Discovery of Clinical Candidate CEP-37440, a Selective Inhibitor of Focal Adhesion Kinase (FAK) and Anaplastic Lymphoma Kinase (ALK)

  • J Med Chem. 2016 Aug 25;59(16):7478-96. doi: 10.1021/acs.jmedchem.6b00487.
Gregory R Ott 1,  Mangeng Cheng 1,  Keith S Learn 1,  Jason Wagner 1,  Diane E Gingrich 1,  Joseph G Lisko 1,  Matthew Curry 1,  Eugen F Mesaros 1,  Arup K Ghose 1,  Matthew R Quail 1,  Weihua Wan 1,  Lihui Lu 1,  Pawel Dobrzanski 1,  Mark S Albom 1,  Thelma S Angeles 1,  Kevin Wells-Knecht 1,  Zeqi Huang 1,  Lisa D Aimone 1,  Elizabeth Bruckheimer 2,  Nathan Anderson 2,  Jay Friedman 2,  Sandra V Fernandez 3,  Mark A Ator 1,  Bruce A Ruggeri 1,  Bruce D Dorsey 1
Affiliations

Affiliations

  • 1 Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
  • 2 Champions Oncology, Inc. , One University Plaza, Suite 307, Hackensack, New Jersey 07601, United States.
  • 3 Thomas Jefferson University , 233 South 10th Street, 1002 BLSB, Philadelphia, Pennsylvania 19107, United States.
PMID: 27527804 DOI: 10.1021/acs.jmedchem.6b00487
Abstract

Analogues structurally related to anaplastic lymphoma kinase (ALK) inhibitor 1 were optimized for metabolic stability. The results from this endeavor not only led to improved metabolic stability, pharmacokinetic parameters, and in vitro activity against clinically derived resistance mutations but also led to the incorporation of activity for focal adhesion kinase (FAK). FAK activation, via amplification and/or overexpression, is characteristic of multiple invasive solid tumors and metastasis. The discovery of the clinical stage, dual FAK/ALK inhibitor 27b, including details surrounding SAR, in vitro/in vivo pharmacology, and pharmacokinetics, is reported herein.

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