title: Selectivity switch between FAK and Pyk2: Macrocyclization of FAK inhibitors improves Pyk2 potency.
abstract: Herein, we describe the synthesis of Pyk2 inhibitors via macrocyclization of FAK and dual Pyk2-FAK inhibitors. We identified macrocycle 25a as a highly potent Pyk2 inhibitor (IC50=0.7nM), with ∼175-fold improvement in Pyk2 potency as compared to its acyclic counterpart. In many cases, macrocyclization improved Pyk2 potency while weakening FAK potency, thereby improving the Pyk2/FAK selectivity ratio for this structural class of inhibitors. Various macrocyclic linkers were studied in an attempt to optimize Pyk2 selectivity. We observed macrocyclic atropisomerism during the synthesis of 19-membered macrocycles 10a-d, and successfully obtained crystallographic evidence of one atropisomer (10a-AtropB) preferentially bound to Pyk2.
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. Electronic address: Julie.Farand@gilead.com.
authors.forename: Julie
authors.initials: J
authors.lastname: Farand
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mai
authors.affiliation: Department of Structural Chemistry, Gilead Sciences, Inc., 199 East Blaine Street, Seattle, WA 98102, USA.
authors.forename: Jayaraman
authors.initials: J
authors.lastname: Chandrasekhar
authors.affiliation: Department of Structural Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Zachary E
authors.initials: ZE
authors.lastname: Newby
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, Inc., 199 East Blaine Street, Seattle, WA 98102, USA.
authors.forename: Josh
authors.initials: J
authors.lastname: Van Veldhuizen
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, Inc., 199 East Blaine Street, Seattle, WA 98102, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Loyer-Drew
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Chandrasekar
authors.initials: C
authors.lastname: Venkataramani
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Guerrero
authors.affiliation: Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Kwok
authors.affiliation: Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Zherebina
authors.affiliation: Department of Drug Metabolism, Gilead Sciences, Inc., 199 East Blaine Street, Seattle, WA 98102, USA.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Wilbert
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Zablocki
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, Inc., 199 East Blaine Street, Seattle, WA 98102, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Phillips
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Watkins
authors.affiliation: Department of Biology, Gilead Sciences, Inc., 199 East Blaine Street, Seattle, WA 98102, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Mourey
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Notte
mesh_terms: D000818:Animals; D003500:Cyclization; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011505:Protein-Tyrosine Kinases / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D046911:Macromolecular Substances; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2
keywords: Atropisomer; FAK; Glioblastoma; Macrocycle; Pyk2