Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, variants, or PubMed publications.

Have questions, comments or suggestions? - Let us know!

Email us at : ckbsupport@jax.org

Ref Type Journal Article
PMID (27682507)
Authors Crawford TD, Romero FA, Lai KW, Tsui V, Taylor AM, de Leon Boenig G, Noland CL, Murray J, Ly J, Choo EF, Hunsaker TL, Chan EW, Merchant M, Kharbanda S, Gascoigne KE, Kaufman S, Beresini MH, Liao J, Liu W, Chen KX, Chen Z, Conery AR, Côté A, Jayaram H, Jiang Y, Kiefer JR, Kleinheinz T, Li Y, Maher J, Pardo E, Poy F, Spillane KL, Wang F, Wang J, Wei X, Xu Z, Xu Z, Yen I, Zawadzke L, Zhu X, Bellon S, Cummings R, Cochran AG, Albrecht BK, Magnuson S
Title Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300.
Journal Journal of medicinal chemistry
Vol 59
Issue 23
Date 2016 Dec 08
URL
Abstract Text The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target of much recent interest in cancer and immune system regulation. A co-crystal structure of a ligand-efficient screening hit and the CBP bromodomain guided initial design targeting the LPF shelf, ZA loop, and acetylated lysine binding regions. Structure-activity relationship studies allowed us to identify a more potent analogue. Optimization of permeability and microsomal stability and subsequent improvement of mouse hepatocyte stability afforded 59 (GNE-272, TR-FRET IC50 = 0.02 μM, BRET IC50 = 0.41 μM, BRD4(1) IC50 = 13 μM) that retained the best balance of cell potency, selectivity, and in vivo PK. Compound 59 showed a marked antiproliferative effect in hematologic cancer cell lines and modulates MYC expression in vivo that corresponds with antitumor activity in an AML tumor model.

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
GNE-272 GNE-272 4 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
GNE-272 GNE-272 is an inhibitor targeting the bromodomains of CREBBP and EP300, which subsequently prevents MYC expression, thereby potentially resulting in anti-proliferative effects and tumor growth inhibition (PMID: 27682507).
Gene 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 leukemia not applicable GNE-272 Preclinical - Cell culture Actionable In a preclinical study, GNE-272 treatment resulted in anti-proliferative activity in leukemia cell lines in culture (PMID: 27682507). 27682507
Unknown unknown lymphoma not applicable GNE-272 Preclinical - Cell culture Actionable In a preclinical study, GNE-272 treatment resulted in anti-proliferative activity in lymphoma cell lines in culture (PMID: 27682507). 27682507
Unknown unknown multiple myeloma not applicable GNE-272 Preclinical - Cell culture Actionable In a preclinical study, GNE-272 treatment resulted in anti-proliferative activity in multiple myeloma cell lines in culture (PMID: 27682507). 27682507
Unknown unknown acute myeloid leukemia not applicable GNE-272 Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with GNE-272 in acute myeloid leukemia xenograft models resulted in tumor growth inhibition at all doses, and at the highest dose led to a complete response in one of the eight tested mouse models (PMID: 27682507). 27682507