Into Deep Water: Optimizing BCL6 Inhibitors by Growing into a Solvated Pocket.
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Date
2021-12-09ICR Author
Author
Lloyd, MG
Huckvale, R
Cheung, K-MJ
Rodrigues, MJ
Collie, GW
Pierrat, OA
Gatti Iou, M
Carter, M
Davis, OA
McAndrew, PC
Gunnell, E
Le Bihan, Y-V
Talbot, R
Henley, AT
Johnson, LD
Hayes, A
Bright, MD
Raynaud, FI
Meniconi, M
Burke, R
van Montfort, RLM
Rossanese, OW
Bellenie, BR
Hoelder, S
Type
Journal Article
Metadata
Show full item recordAbstract
We describe the optimization of modestly active starting points to potent inhibitors of BCL6 by growing into a subpocket, which was occupied by a network of five stably bound water molecules. Identifying potent inhibitors required not only forming new interactions in the subpocket but also perturbing the water network in a productive, potency-increasing fashion while controlling the physicochemical properties. We achieved this goal in a sequential manner by systematically probing the pocket and the water network, ultimately achieving a 100-fold improvement of activity. The most potent compounds displaced three of the five initial water molecules and formed hydrogen bonds with the remaining two. Compound 25 showed a promising profile for a lead compound with submicromolar inhibition of BCL6 in cells and satisfactory pharmacokinetic (PK) properties. Our work highlights the importance of finding productive ways to perturb existing water networks when growing into solvent-filled protein pockets.
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Subject
Humans
Antineoplastic Agents
Crystallography, X-Ray
Structure-Activity Relationship
Drug Design
Hydrogen Bonding
Solubility
Proto-Oncogene Proteins c-bcl-6
Research team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 4 (including Analytical Chemistry)
Target Evaluation and Molecular Therapeutics
Hit Discovery & Structural Design
Language
eng
Date accepted
2021-11-30
Citation
Journal of medicinal chemistry, 2021, 64 (23), pp. 17079 - 17097
Publisher
AMER CHEMICAL SOC