| [https://www.uniprot.org/uniprot/CBP_HUMAN CBP_HUMAN] Acetylates histones, giving a specific tag for transcriptional activation. Also acetylates non-histone proteins, like NCOA3 and FOXO1. Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1 in the presence of EP300.<ref>PMID:9707565</ref> <ref>PMID:11154691</ref> <ref>PMID:12738767</ref> <ref>PMID:12929931</ref> | | [https://www.uniprot.org/uniprot/CBP_HUMAN CBP_HUMAN] Acetylates histones, giving a specific tag for transcriptional activation. Also acetylates non-histone proteins, like NCOA3 and FOXO1. Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1 in the presence of EP300.<ref>PMID:9707565</ref> <ref>PMID:11154691</ref> <ref>PMID:12738767</ref> <ref>PMID:12929931</ref> |
| 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 muM, BRET IC50 = 0.41 muM, BRD4(1) IC50 = 13 muM) 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.
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| Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300.,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, Cote 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 J Med Chem. 2016 Sep 28. PMID:27682507<ref>PMID:27682507</ref>
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