title: Back pocket flexibility provides group II p21-activated kinase (PAK) selectivity for type I 1/2 kinase inhibitors.
abstract: Structure-based methods were used to design a potent and highly selective group II p21-activated kinase (PAK) inhibitor with a novel binding mode, compound 17. Hydrophobic interactions within a lipophilic pocket past the methionine gatekeeper of group II PAKs approached by these type I 1/2 binders were found to be important for improving potency. A structure-based hypothesis and strategy for achieving selectivity over group I PAKs, and the broad kinome, based on unique flexibility of this lipophilic pocket, is presented. A concentration-dependent decrease in tumor cell migration and invasion in two triple-negative breast cancer cell lines was observed with compound 17.
authors.affiliation: Department of Discovery Chemistry, ‡Department of Translational Oncology, △Department of Pathology, §Department of Drug Metabolism and Pharmacokinetics, ∥Department of Biochemical and Cellular Pharmacology, and ⊥Department of Structural Biology, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Staben
authors.forename: Jianwen A
authors.initials: JA
authors.lastname: Feng
authors.forename: Karen
authors.initials: K
authors.lastname: Lyle
authors.forename: Marcia
authors.initials: M
authors.lastname: Belvin
authors.forename: Jason
authors.initials: J
authors.lastname: Boggs
authors.forename: Jason D
authors.initials: JD
authors.lastname: Burch
authors.forename: Ching-ching
authors.initials: CC
authors.lastname: Chua
authors.forename: Haifeng
authors.initials: H
authors.lastname: Cui
authors.forename: Antonio G
authors.initials: AG
authors.lastname: DiPasquale
authors.forename: Lori S
authors.initials: LS
authors.lastname: Friedman
authors.forename: Christopher
authors.initials: C
authors.lastname: Heise
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.forename: Adrian
authors.initials: A
authors.lastname: Kotey
authors.forename: Robert
authors.initials: R
authors.lastname: Mintzer
authors.forename: Angela
authors.initials: A
authors.lastname: Oh
authors.forename: David Allen
authors.initials: DA
authors.lastname: Roberts
authors.forename: Lionel
authors.initials: L
authors.lastname: Rouge
authors.forename: Joachim
authors.initials: J
authors.lastname: Rudolph
authors.forename: Christine
authors.initials: C
authors.lastname: Tam
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.forename: Yisong
authors.initials: Y
authors.lastname: Xiao
authors.forename: Amy
authors.initials: A
authors.lastname: Young
authors.forename: Yamin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Hoeflich
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D064726:Triple Negative Breast Neoplasms; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: C587762:1-(2-(1-(2-aminopyrimidin-4-yl)-2-((2-methoxyethyl)amino)-1H-1,3-benzodiazol-6-yl)ethynyl)cyclohexan-1-ol; D000480:Alkynes; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D011743:Pyrimidines; D054462:p21-Activated Kinases