Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors.
Date
2022-06-23ICR Author
Author
Davis, OA
Cheung, K-MJ
Brennan, A
Lloyd, MG
Rodrigues, MJ
Pierrat, OA
Collie, GW
Le Bihan, Y-V
Huckvale, R
Harnden, AC
Varela, A
Bright, MD
Eve, P
Hayes, A
Henley, AT
Carter, MD
McAndrew, PC
Talbot, R
Burke, R
van Montfort, RLM
Raynaud, FI
Rossanese, OW
Meniconi, M
Bellenie, BR
Hoelder, S
Type
Journal Article
Metadata
Show full item recordAbstract
To identify new chemical series with enhanced binding affinity to the BTB domain of B-cell lymphoma 6 protein, we targeted a subpocket adjacent to Val18. With no opportunities for strong polar interactions, we focused on attaining close shape complementarity by ring fusion onto our quinolinone lead series. Following exploration of different sized rings, we identified a conformationally restricted core which optimally filled the available space, leading to potent BCL6 inhibitors. Through X-ray structure-guided design, combined with efficient synthetic chemistry to make the resulting novel core structures, a >300-fold improvement in activity was obtained by the addition of seven heavy atoms.
Collections
Subject
BTB-POZ Domain
Protein Binding
Proto-Oncogene Proteins c-bcl-6
Research team
Hit Discov Struct Design
Clinical Pharma & Trials
Directorate Canc Ther
Medicinal Chemistry 4
Language
eng
Date accepted
2021-12-01
License start date
2022-06-23
Citation
Journal of Medicinal Chemistry, 2022, 65 (12), pp. 8169 - 8190
Publisher
AMER CHEMICAL SOC