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 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.
Highlights
Diffuse large B-cell lymphomas (DLBCLs) are the most common subtype of non-Hodgkin lymphoma.[1]
Most B-cell lymphomas arise from germinal center B-cells.[5−7] Once oncogenic, the tumor relies on the sustained expression of BCL6.8 In the case of DLBCL, blocking the interaction between BCL6 and its corepressors enables the re-expression of repressed genes, which leads to the continuation of B-cell differentiation and cell death.[9]
We report the rescaffolding of benzimidazolone CCT365386,17 1, to identify quinolinone 2 and the optimization of this compound by growing the core into an extended subpocket of the corepressor binding domain
Summary
Diffuse large B-cell lymphomas (DLBCLs) are the most common subtype of non-Hodgkin lymphoma.[1]. This highlights potential therapeutic efficacy for inhibitors of this BCL6 protein−protein interaction
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