Discovery of New Inhibitors of Cdc25B Dual Specificity Phosphatases by Structure-Based Virtual Screening

Cell division cycle 25 (Cdc25) proteins are highly conserved
dual
specificity phosphatases that regulate cyclin-dependent kinases and
represent attractive drug targets for anticancer therapies. To discover
more potent and diverse inhibitors of Cdc25 biological activity, virtual
screening was performed by docking 2.1 million compounds into the
Cdc25B active site. An initial subset of top-ranked compounds was
selected and assayed, and 15 were found to have enzyme inhibition
activity at micromolar concentration. Among these, four structurally
diverse inhibitors with a different inhibition profile were found
to inhibit human MCF-7, PC-3, and K562 cancer cell proliferation and
significantly affect the cell cycle progression. A subsequent hierarchical
similarity search with the most active reversible Cdc25B inhibitor
found led to the identification of an additional set of 19 ligands,
three of which were confirmed as Cdc25B inhibitors with IC50 values of 7.9, 4.2, and 9.9 μM, respectively.

细胞分裂周期蛋白25（Cell division cycle 25, Cdc25）是一类高度保守的双特异性磷酸酶（dual specificity phosphatases），可调控细胞周期蛋白依赖性激酶（cyclin-dependent kinases），同时也是抗癌治疗领域极具吸引力的药物靶点。为发掘活性更强、结构更多样的Cdc25生物活性抑制剂，研究团队通过分子对接（docking）的方式将210万种化合物对接到Cdc25B的活性位点中，开展了虚拟筛选（virtual screening）。研究人员初步选取排名靠前的化合物子集进行活性检测，最终发现15种化合物在微摩尔浓度下具备酶抑制活性。其中4种结构迥异、抑制谱各不相同的抑制剂，可抑制人源MCF-7、PC-3及K562癌细胞的增殖，并对细胞周期进程产生显著影响。后续针对筛选得到的活性最强的可逆性Cdc25B抑制剂开展层级相似性检索（hierarchical similarity search），又鉴定出19种配体，其中3种被证实为Cdc25B抑制剂，其半最大抑制浓度（IC50）分别为7.9 μM、4.2 μM及9.9 μM。