학술논문
Into Deep Water: Optimizing BCL6 Inhibitors by Growing into a Solvated Pocket
Document Type
Article
Author
Lloyd, Matthew G.; Huckvale, Rosemary; Cheung, Kwai-Ming J.; Rodrigues, Matthew J.; Collie, Gavin W.; Pierrat, Olivier A.; Gatti Iou, Mahad; Carter, Michael; Davis, Owen A.; McAndrew, P. Craig; Gunnell, Emma; Le Bihan, Yann-Vaï; Talbot, Rachel; Henley, Alan T.; Johnson, Louise D.; Hayes, Angela; Bright, Michael D.; Raynaud, Florence I.; Meniconi, Mirco; Burke, Rosemary; van Montfort, Rob L. M.; Rossanese, Olivia W.; Bellenie, Benjamin R.; Hoelder, Swen
Source
Journal of Medicinal Chemistry; December 2021, Vol. 64 Issue: 23 p17079-17097, 19p
Subject
Language
ISSN
00222623; 15204804
Abstract
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 25showed 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.