title: Discovery and characterization of novel allosteric FAK inhibitors.
abstract: Focal adhesion kinase (FAK) regulates cell survival and proliferation pathways. Here we report the discovery of a highly selective series of 1,5-dihydropyrazolo[4,3-c][2,1]benzothiazines that demonstrate a novel mode of allosteric inhibition of FAK. These compounds showed slow dissociation from unphosphorylated FAK and were noncompetitive with ATP after long preincubation. Co-crystal structural analysis revealed that the compounds target a novel allosteric site within the C-lobe of the kinase domain, which induces disruption of ATP pocket formation leading to the inhibition of kinase activity. The potency of allosteric inhibition was reduced by phosphorylation of FAK. Coupled SAR analysis revealed that N-substitution of the fused pyrazole is critical to achieve allosteric binding and high selectivity among kinases.
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Misa
authors: M
authors: Iwatani
authors: Hidehisa
authors: H
authors: Iwata
authors: Atsutoshi
authors: A
authors: Okabe
authors: Robert J
authors: RJ
authors: Skene
authors: Naoki
authors: N
authors: Tomita
authors: Yoko
authors: Y
authors: Hayashi
authors: Yoshio
authors: Y
authors: Aramaki
authors: David J
authors: DJ
authors: Hosfield
authors: Akira
authors: A
authors: Hori
authors: Atsuo
authors: A
authors: Baba
authors: Hiroshi
authors: H
authors: Miki
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D013843:Thiazines; D051416:Focal Adhesion Protein-Tyrosine Kinases