title: Discovery of Clinical Candidate CEP-37440, a Selective Inhibitor of Focal Adhesion Kinase (FAK) and Anaplastic Lymphoma Kinase (ALK).
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.
authors.affiliation: Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Ott
authors.affiliation: Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Mangeng
authors.initials: M
authors.lastname: Cheng
authors.affiliation: Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Keith S
authors.initials: KS
authors.lastname: Learn
authors.affiliation: Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Wagner
authors.affiliation: Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Gingrich
authors.affiliation: Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Lisko
authors.affiliation: Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Curry
authors.affiliation: Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Eugen F
authors.initials: EF
authors.lastname: Mesaros
authors.affiliation: Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Arup K
authors.initials: AK
authors.lastname: Ghose
authors.affiliation: Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Quail
authors.affiliation: Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Weihua
authors.initials: W
authors.lastname: Wan
authors.affiliation: Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Lihui
authors.initials: L
authors.lastname: Lu
authors.affiliation: Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Pawel
authors.initials: P
authors.lastname: Dobrzanski
authors.affiliation: Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Albom
authors.affiliation: Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Thelma S
authors.initials: TS
authors.lastname: Angeles
authors.affiliation: Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wells-Knecht
authors.affiliation: Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Zeqi
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.affiliation: Champions Oncology, Inc. , One University Plaza, Suite 307, Hackensack, New Jersey 07601, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bruckheimer
authors.affiliation: Champions Oncology, Inc. , One University Plaza, Suite 307, Hackensack, New Jersey 07601, United States.
authors.forename: Nathan
authors.initials: N
authors.lastname: Anderson
authors.affiliation: Champions Oncology, Inc. , One University Plaza, Suite 307, Hackensack, New Jersey 07601, United States.
authors.forename: Jay
authors.initials: J
authors.lastname: Friedman
authors.affiliation: Thomas Jefferson University , 233 South 10th Street, 1002 BLSB, Philadelphia, Pennsylvania 19107, United States.
authors.forename: Sandra V
authors.initials: SV
authors.lastname: Fernandez
authors.affiliation: Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ator
authors.affiliation: Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Ruggeri
authors.affiliation: Teva Branded Pharmaceutical Products R&D , 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Dorsey
mesh_terms: D000284:Administration, Oral; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001567:Benzocycloheptenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D001567:Benzocycloheptenes; C000611391:CEP-37440; D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human