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|Ref Type||Journal Article|
|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|
|Date||2016 Dec 08|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|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|