title: An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells.
abstract: The KDM5 family of histone demethylases catalyzes the demethylation of histone H3 on lysine 4 (H3K4) and is required for the survival of drug-tolerant persister cancer cells (DTPs). Here we report the discovery and characterization of the specific KDM5 inhibitor CPI-455. The crystal structure of KDM5A revealed the mechanism of inhibition of CPI-455 as well as the topological arrangements of protein domains that influence substrate binding. CPI-455 mediated KDM5 inhibition, elevated global levels of H3K4 trimethylation (H3K4me3) and decreased the number of DTPs in multiple cancer cell line models treated with standard chemotherapy or targeted agents. These findings show that pretreatment of cancer cells with a KDM5-specific inhibitor results in the ablation of a subpopulation of cancer cells that can serve as the founders for therapeutic relapse.
authors.affiliation: Genentech Inc., South San Francisco, California, USA.
authors.forename: Maia
authors.initials: M
authors.lastname: Vinogradova
authors.affiliation: Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Victor S
authors.initials: VS
authors.lastname: Gehling
authors.affiliation: Genentech Inc., South San Francisco, California, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Gustafson
authors.affiliation: Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Shilpi
authors.identifier: 0000-0001-5133-3612
authors.initials: S
authors.lastname: Arora
authors.affiliation: Genentech Inc., South San Francisco, California, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Tindell
authors.affiliation: Genentech Inc., South San Francisco, California, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Wilson
authors.affiliation: Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Kaylyn E
authors.initials: KE
authors.lastname: Williamson
authors.affiliation: Genentech Inc., South San Francisco, California, USA.
authors.forename: Gulfem D
authors.initials: GD
authors.lastname: Guler
authors.affiliation: Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Pranoti
authors.initials: P
authors.lastname: Gangurde
authors.affiliation: Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Wanda
authors.initials: W
authors.lastname: Manieri
authors.affiliation: Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Busby
authors.affiliation: Genentech Inc., South San Francisco, California, USA.
authors.forename: E Megan
authors.initials: EM
authors.lastname: Flynn
authors.affiliation: Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Lan
authors.affiliation: Genentech Inc., South San Francisco, California, USA.
authors.forename: Hyo-Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Shobu
authors.initials: S
authors.lastname: Odate
authors.affiliation: Genentech Inc., South San Francisco, California, USA.
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Cochran
authors.affiliation: Genentech Inc., South San Francisco, California, USA.
authors.forename: Yichin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Genentech Inc., South San Francisco, California, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wongchenko
authors.affiliation: Genentech Inc., South San Francisco, California, USA.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Genentech Inc., South San Francisco, California, USA.
authors.forename: Tommy K
authors.initials: TK
authors.lastname: Cheung
authors.affiliation: Genentech Inc., South San Francisco, California, USA.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Maile
authors.affiliation: Genentech Inc., South San Francisco, California, USA.
authors.forename: Ted
authors.initials: T
authors.lastname: Lau
authors.affiliation: Genentech Inc., South San Francisco, California, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Costa
authors.affiliation: Genentech Inc., South San Francisco, California, USA.
authors.forename: Ganapati V
authors.initials: GV
authors.lastname: Hegde
authors.affiliation: Genentech Inc., South San Francisco, California, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Jackson
authors.affiliation: Genentech Inc., South San Francisco, California, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Pitti
authors.affiliation: Genentech Inc., South San Francisco, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Arnott
authors.affiliation: Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Bailey
authors.affiliation: Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Bellon
authors.affiliation: Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Cummings
authors.affiliation: Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Albrecht
authors.affiliation: Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
authors.affiliation: Genentech Inc., South San Francisco, California, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Kiefer
authors.affiliation: Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Trojer
authors.affiliation: Genentech Inc., South San Francisco, California, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Classon
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D056485:Retinoblastoma-Binding Protein 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C070050:KDM5A protein, human; D056485:Retinoblastoma-Binding Protein 2