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发现BAY 2666605,一种用于PDE3A和SLFN12的分子合剂

Timothy A Lewis¹, Manuel Ellermann², Charlotte Kopitz²

¹Center for the Science of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.

ACS medicinal chemistry letters

|October 16, 2024

概括

一些固酶3 (PDE3) 抑制剂可以杀死表达PDE3A和SLFN12的癌细胞. 这种机制涉及诱导蛋白质-蛋白质相互作用,触发SLFN12tRNase活性,从而导致像BAY 2666605.5这样的新药候选物.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
药用化学医学化学

背景情况:

固醇酶3 (PDE3) 抑制剂的一个子集表现出抗癌性质.
这些抑制剂向表达PDE3A和SLFN12的癌细胞.

研究的目的:

发现新型化合物,诱导PDE3A和SLFN12.12之间的蛋白质蛋白相互作用.
开发用于癌症治疗的强效和代谢稳定的PDE3抑制剂.
为了确定癌症治疗的临床可行的候选药物.

主要方法:

发现了工具化合物DNMDP.
优化DNMDP到BRD9500,证明细胞功效和体内活性.
合成和测试类似物以提高代谢稳定性和减少PDE3抑制.
确定BAY 2666605作为一个临床优化的化合物.

主要成果:

确定了原型化合物DNMDP的存在.
BRD9500在癌细胞中显示出强度,并在体内瘤模型中显示出有效性.
模拟开发导致了更好的代谢稳定性和维持细胞活动.
BAY 2666605成为一种高度优化的临床评估化合物.

结论:

通过PDE3A-SLFN12相互作用,PDE3抑制剂可以被设计成通过选择性杀死癌细胞.
BAY 2666605是临床开发的一个有前途的治疗候选药物.
这项研究突出了针对性癌症治疗的新机制.

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