7OKK

Crystal structure of human BCL6 BTB domain in complex with compound 12e

Summary for 7OKK

• Entry DOI: 10.2210/pdb7okk/pdb
• Descriptor: B-cell lymphoma 6 protein, ALA-TRP-VAL-ILE-PRO-ALA, 2-[[6-[(2-chloranyl-3-cyano-pyridin-4-yl)amino]-2-oxidanylidene-1H-quinolin-4-yl]amino]-N-methyl-ethanamide, ... (6 entities in total)
• Functional Keywords: cancer, lymphoma, inhibitor, transcription
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 15797.16

Authors

Collie, G.W.,Le Bihan, Y.-V.,van Montfort, R.L.M. (deposition date: 2021-05-17, release date: 2021-12-08, Last modification date: 2024-01-31)

Primary citation

Lloyd, M.G.,Huckvale, R.,Cheung, K.J.,Rodrigues, M.J.,Collie, G.W.,Pierrat, O.A.,Gatti Iou, M.,Carter, M.,Davis, O.A.,McAndrew, P.C.,Gunnell, E.,Le Bihan, Y.V.,Talbot, R.,Henley, A.T.,Johnson, L.D.,Hayes, A.,Bright, M.D.,Raynaud, F.I.,Meniconi, M.,Burke, R.,van Montfort, R.L.M.,Rossanese, O.W.,Bellenie, B.R.,Hoelder, S.
Into Deep Water: Optimizing BCL6 Inhibitors by Growing into a Solvated Pocket.
J.Med.Chem., 64:17079-17097, 2021

PubMed 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 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.

PubMed: 34846884
DOI: 10.1021/acs.jmedchem.1c00946

Experimental method

X-RAY DIFFRACTION (2.05 Å)