7LZQ

Crystal structure of the BCL6 BTB domain in complex with OICR-4425

Summary for 7LZQ

• Entry DOI: 10.2210/pdb7lzq/pdb
• Related: 7LWE 7LWF 7LWG
• Descriptor: B-cell lymphoma 6 protein, N-(3-chloropyridin-4-yl)-2-(5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)acetamide, DIMETHYL SULFOXIDE, ... (4 entities in total)
• Functional Keywords: immunity, inflammatory response, transcription repressor, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 15197.03

Authors

Kuntz, D.A.,Prive, G.G. (deposition date: 2021-03-10, release date: 2022-08-17, Last modification date: 2023-10-25)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.71 Å)