Dorado Tony E, de León Pablo, Begum Asma, Liu Hester, Chen Daming, Rajeshkumar N V, Rey-Rodriguez Romain, Hoareau-Aveilla Coralie, Alcouffe Chantal, Laiho Marikki, Barrow James C
Department of Chemistry, Johns Hopkins University, Baltimore, Maryland 21218, United States.
Lieber Institute for Brain Development, 855 North Wolfe Street Suite 300, Baltimore, Maryland 21205, United States.
ACS Med Chem Lett. 2022 Mar 18;13(4):608-614. doi: 10.1021/acsmedchemlett.1c00660. eCollection 2022 Apr 14.
RNA polymerase I (Pol I) transcribes ribosomal DNA (rDNA) into the 47S ribosomal RNA (rRNA) precursor. Further processing produces the 28S, 5.8S, and 18S rRNAs that are assembled into mature ribosomes. Many cancers exhibit higher Pol I transcriptional activity, reflecting a need for increased ribosome biogenesis and protein synthesis and making the inhibition of this process an attractive therapeutic strategy. Lead molecule BMH-21 () has been established as a Pol I inhibitor by affecting the destruction of RPA194, the Pol I large catalytic subunit. A previous structure-activity relationship (SAR) study uncovered key pharmacophores, but activity was constrained within a tight chemical space. This work details further SAR efforts that have yielded new scaffolds and improved off-target activity while retaining the desired RPA194 degradation potency. Pharmacokinetic profiling was obtained and provides a starting point for further optimization. New compounds present additional opportunities for the development of Pol I inhibitory cancer therapies.
RNA聚合酶I（Pol I）将核糖体DNA（rDNA）转录为47S核糖体RNA（rRNA）前体。进一步加工产生28S、5.8S和18S rRNA，它们组装成成熟核糖体。许多癌症表现出较高的Pol I转录活性，这反映了对增加核糖体生物合成和蛋白质合成的需求，使得抑制这一过程成为一种有吸引力的治疗策略。先导分子BMH-21（）通过影响Pol I的大型催化亚基RPA194的降解而被确立为一种Pol I抑制剂。先前的构效关系（SAR）研究发现了关键药效团，但活性被限制在一个狭窄的化学空间内。这项工作详细介绍了进一步的SAR研究成果，这些研究产生了新的骨架并改善了脱靶活性，同时保留了所需的RPA194降解效力。获得了药代动力学概况，为进一步优化提供了一个起点。新化合物为开发Pol I抑制性癌症治疗提供了更多机会。
