Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors.
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Authors
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
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
Document Type
Journal Article
Date
2022-06-23
Date Accepted
2021-12-01
Abstract
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.
Citation
Journal of Medicinal Chemistry, 2022, 65 (12), pp. 8169 - 8190
Source Title
Journal of Medicinal Chemistry
Publisher
AMER CHEMICAL SOC
ISSN
0022-2623
eISSN
1520-4804
1520-4804
1520-4804
Collections
Research Team
Hit Discov Struct Design
Clinical Pharma & Trials
Directorate Canc Ther
Medicinal Chemistry 4
Clinical Pharma & Trials
Directorate Canc Ther
Medicinal Chemistry 4