Open Innovation Center for Drug Discovery, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
J Med Chem. 2012 Jun 14;55(11):5151-64. doi: 10.1021/jm3001289. Epub 2012 May 17.
Serine/threonine kinase PIM1 is an emerging therapeutic target for hematopoietic and prostate cancer therapy. To develop a novel PIM1 inhibitor, we focused on 1, a metabolically labile, nonselective kinase inhibitor discovered in our previous screening study. We adopted a rational optimization strategy based mainly on structural information for the PIM1-1 complex to improve the potency and selectivity. This approach afforded the potent and metabolically stable PIM1-selective inhibitor 14, which shows only a marginal increase in molecular weight compared with 1 but has a significantly decreased cLogP. The validity of our design concept was confirmed by X-ray structure analysis. In a cellular study, 14 potently inhibited the growth of human leukemia cell line MV4-11 but had a negligible effect on the growth of WI-38 (surrogate for general toxicity). These results demonstrate the effectiveness of our design strategy for evolving the screening-hit compound 1 into a novel type of PIM1 inhibitor, 14.
丝氨酸/苏氨酸激酶 PIM1 是血液系统肿瘤和前列腺癌治疗的一个新兴治疗靶点。为了开发新型 PIM1 抑制剂，我们专注于我们之前的筛选研究中发现的代谢不稳定的非选择性激酶抑制剂 1。我们主要基于 PIM1-1 复合物的结构信息采用了合理的优化策略来提高其活性和选择性。该方法得到了活性更高且代谢更稳定的 PIM1 选择性抑制剂 14，与 1 相比，其分子量仅略有增加，但 cLogP 显著降低。X 射线结构分析证实了我们设计理念的有效性。在细胞研究中，14 能够强烈抑制人白血病细胞系 MV4-11 的生长，但对 WI-38（一般毒性的替代物）的生长几乎没有影响。这些结果表明，我们的设计策略可将筛选得到的化合物 1 转化为新型 PIM1 抑制剂 14，这是有效的。
