Servier Research Institute of Medicinal Chemistry, Záhony u. 7., Budapest H-1031, Hungary.
Institute de Recherche Servier, 22 Route 128, Gif-sur-Yvette 91190, France.
J Med Chem. 2024 Nov 14;67(21):18993-19009. doi: 10.1021/acs.jmedchem.4c01472. Epub 2024 Oct 23.
Inhibition of ubiquitin-specific protease 7, USP7, has been proposed as a mechanism to affect many disease processes, primarily those implicated in oncology. The bound crystal structure of a published high-throughput screening hit with low-micromolar affinity for USP7 identified three regions of the compound for structure-guided optimization. Replacing one side of the compound with different aromatic moieties gave little improvement in affinity, and the central piperidine could not be improved. However, the binding site for the other side of the compound was poorly defined in the crystal structure, which suggested a wide variety of synthetically accessible options for optimization. These were assessed by screening reaction mixtures that introduced different substituents to this other side. Subsequent optimization led to a compound with low-nanomolar affinity for USP7, which showed target engagement in tumors, was tolerated in mice, and showed efficacy in xenograft models.
抑制泛素特异性蛋白酶 7（USP7）已被提出作为影响许多疾病过程的机制，主要是那些与肿瘤学相关的疾病过程。结合高亲和力的 USP7 发表的高通量筛选命中的结合晶体结构确定了化合物的三个结构导向优化区域。用不同的芳香族取代基替代化合物的一侧几乎没有改善亲和力，并且不能改善中央哌啶。然而，在晶体结构中，化合物的另一侧的结合位点定义不明确，这表明有广泛的合成上可接近的优化选择。通过筛选引入该另一侧的不同取代基的反应混合物来评估这些选择。随后的优化导致了对 USP7 具有低纳摩尔亲和力的化合物，该化合物在肿瘤中显示出靶标结合，在小鼠中耐受，并且在异种移植模型中显示出疗效。
