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.

中文翻译：

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进入深水区：通过发展成溶剂化口袋来优化 BCL6 抑制剂


我们描述了通过生长成一个由五个稳定结合的水分子组成的网络占据的子口袋，对 BCL6 的有效抑制剂进行适度活性的优化。识别有效的抑制剂不仅需要在子口袋中形成新的相互作用，而且还需要以高效、增强效力的方式扰动水网络，同时控制物理化学性质。我们通过系统地探测口袋和水网络，以连续的方式实现了这一目标，最终实现了活性提高 100 倍。最有效的化合物取代了五个初始水分子中的三个，并与其余两个形成氢键。化合物25作为先导化合物具有良好的前景，对细胞中的 BCL6 具有亚微摩尔抑制作用，并且具有令人满意的药代动力学 (PK) 特性。我们的工作强调了在生长成充满溶剂的蛋白质口袋时找到扰乱现有水网络的有效方法的重要性。