Reference Detail

Ref Type Journal Article
PMID (27214401)
Authors Vinogradova M, Gehling VS, Gustafson A, Arora S, Tindell CA, Wilson C, Williamson KE, Guler GD, Gangurde P, Manieri W, Busby J, Flynn EM, Lan F, Kim HJ, Odate S, Cochran AG, Liu Y, Wongchenko M, Yang Y, Cheung TK, Maile TM, Lau T, Costa M, Hegde GV, Jackson E, Pitti R, Arnott D, Bailey C, Bellon S, Cummings RT, Albrecht BK, Harmange JC, Kiefer JR, Trojer P, Classon M
Title An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells.
Journal Nature chemical biology
Vol 12
Issue 7
Date 2016 Jul
URL
Abstract Text 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.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
CPI-455 CPI-455 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
CPI-455 CPI-455 is an inhibitor of KDM5A, KDM5B, and KDM5C, which may reduce cell survival, in particular those cells that are considered drug resistant (PMID: 27214401).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown colon cancer sensitive AZ628 + CPI-455 Preclinical - Cell culture Actionable In a preclinical study, a colon cancer cell line treated with AZ628 demonstrated increased sensitivity when co-treated with CPI-455 in culture, resulting in decreased survival of cells, in particular the cells that eventually develop drug resistance (PMID: 27214401). 27214401
Unknown unknown breast cancer sensitive CPI-455 + Lapatinib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line treated with Tykerb (lapatinib) demonstrated increased sensitivity when co-treated with CPI-455 in culture, resulting in decreased survival of cells, in particular the cells that eventually develop drug resistance (PMID: 27214401). 27214401