8C78

Crystal structure of human BCL6 BTB domain in complex with compound CCT374705

8C78 の概要

• エントリーDOI: 10.2210/pdb8c78/pdb
• 分子名称: B-cell lymphoma 6 protein, (2~{S})-10-[(3-chloranyl-2-fluoranyl-pyridin-4-yl)amino]-2-cyclopropyl-3,3-bis(fluoranyl)-7-methyl-2,4-dihydro-1~{H}-[1,4]oxazepino[2,3-c]quinolin-6-one, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: inhibitor, cancer, lymphoma, transcription
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 17268.97

構造登録者

Le Bihan, Y.-V.,van Montfort, R.L.M. (登録日: 2023-01-13, 公開日: 2023-04-26, 最終更新日: 2024-06-19)

主引用文献

Harnden, A.C.,Davis, O.A.,Box, G.M.,Hayes, A.,Johnson, L.D.,Henley, A.T.,de Haven Brandon, A.K.,Valenti, M.,Cheung, K.J.,Brennan, A.,Huckvale, R.,Pierrat, O.A.,Talbot, R.,Bright, M.D.,Akpinar, H.A.,Miller, D.S.J.,Tarantino, D.,Gowan, S.,de Klerk, S.,McAndrew, P.C.,Le Bihan, Y.V.,Meniconi, M.,Burke, R.,Kirkin, V.,van Montfort, R.L.M.,Raynaud, F.I.,Rossanese, O.W.,Bellenie, B.R.,Hoelder, S.
Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones.
J.Med.Chem., 66:5892-5906, 2023

PubMed Abstract: B-cell lymphoma 6 (BCL6) is a transcriptional repressor and oncogenic driver of diffuse large B-cell lymphoma (DLBCL). Here, we report the optimization of our previously reported tricyclic quinolinone series for the inhibition of BCL6. We sought to improve the cellular potency and exposure of the non-degrading isomer, , of our recently published degrader, . The major limitation of our inhibitors was their high topological polar surface areas (TPSA), leading to increased efflux ratios. Reducing the molecular weight allowed us to remove polarity and decrease TPSA without considerably reducing solubility. Careful optimization of these properties, as guided by pharmacokinetic studies, led to the discovery of , a potent inhibitor of BCL6 with a good profile. Modest efficacy was achieved in a lymphoma xenograft mouse model after oral dosing.

PubMed: 37026591
DOI: 10.1021/acs.jmedchem.3c00155

実験手法

X-RAY DIFFRACTION (1.8 Å)