7LWE

Crystal structure of the BCL6 BTB domain in complex with OICR-7629

7LWE の概要

• エントリーDOI: 10.2210/pdb7lwe/pdb
• 分子名称: B-cell lymphoma 6 protein, N-(3-chloropyridin-4-yl)-2-(3-methyl-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetamide, FORMIC ACID, ... (6 entities in total)
• 機能のキーワード: immunity, inflammatory response, transcription repressor, transcription-inhibitor complex, transcription/inhibitor
• 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: 15319.46

構造登録者

Kuntz, D.A.,Prive, G.G. (登録日: 2021-03-01, 公開日: 2022-03-09, 最終更新日: 2023-10-25)

主引用文献

Mamai, A.,Chau, A.M.,Wilson, B.J.,Watson, I.D.,Joseph, B.B.,Subramanian, P.R.,Morshed, M.M.,Morin, J.A.,Prakesch, M.A.,Lu, T.,Connolly, P.,Kuntz, D.A.,Pomroy, N.C.,Poda, G.,Nguyen, K.,Marcellus, R.,Strathdee, G.,Theriault, B.,Subramaniam, R.,Mohammed, M.,Abibi, A.,Chan, M.,Winston, J.,Kiyota, T.,Undzys, E.,Aman, A.,Austin, N.,Du Jardin, M.,Packman, K.,Phillippar, U.,Attar, R.,Edwards, J.,O'Meara, J.,Uehling, D.E.,Al-Awar, R.,Prive, G.G.,Isaac, M.B.
Discovery of OICR12694: A Novel, Potent, Selective, and Orally Bioavailable BCL6 BTB Inhibitor.
Acs Med.Chem.Lett., 14:199-210, 2023

PubMed Abstract: B cell lymphoma 6 (BCL6), a highly regulated transcriptional repressor, is deregulated in several forms of non-Hodgkin lymphoma (NHL), most notably in diffuse large B-cell lymphoma (DLBCL). The activities of BCL6 are dependent on protein-protein interactions with transcriptional co-repressors. To find new therapeutic interventions addressing the needs of patients with DLBCL, we initiated a program to identify BCL6 inhibitors that interfere with co-repressor binding. A virtual screen hit with binding activity in the high micromolar range was optimized by structure-guided methods, resulting in a novel and highly potent inhibitor series. Further optimization resulted in the lead candidate (OICR12694/JNJ-65234637), a BCL6 inhibitor with low nanomolar DLBCL cell growth inhibition and an excellent oral pharmacokinetic profile. Based on its overall favorable preclinical profile, OICR12694 is a highly potent, orally bioavailable candidate for testing BCL6 inhibition in DLBCL and other neoplasms, particularly in combination with other therapies.

PubMed: 36793435
DOI: 10.1021/acsmedchemlett.2c00502

実験手法

X-RAY DIFFRACTION (1.17 Å)