Chaudhry Sana, Castro Jesus R, Totiger Tulasigeri M, Afaghani Jumana, Khurshid Rabia, Nicholls Miah, Zhang Ziming, Schürer Stephan C, Shah Ashish, Taylor Justin, Feng Yangbo
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida33136, United States.
Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida 33136, United States.
ACS Med Chem Lett. 2024 May 20;15(6):945-949. doi: 10.1021/acsmedchemlett.4c00125. eCollection 2024 Jun 13.
STK17A is a novel uncharacterized member of the death-associated protein family of serine and threonine kinases. Overexpression of STK17A is observed in many cancers. We identified a lead compound that is based on a quinazoline core. Optimizations of the lead compound led to the discovery of potent and selective STK17A/B inhibitors with drug-like properties and oral bioavailability. Compound had an STK17A inhibitory IC of 23 nM. Based on profiling studies against two wild-type kinase panels (375 and 398 kinases, respectively), compound had strong inhibition of both STK17A and STK17B but moderate off-target inhibition only for AAK1, MYLK4, and NEK3/5. In addition, compound had good oral bioavailability, paving the way for in vivo studies against various cancers.
STK17A是丝氨酸和苏氨酸激酶死亡相关蛋白家族中一个未被表征的新成员。在许多癌症中都观察到STK17A的过表达。我们鉴定出一种以喹唑啉为核心的先导化合物。对该先导化合物的优化导致发现了具有类药物性质和口服生物利用度的强效且选择性的STK17A/B抑制剂。化合物的STK17A抑制IC50为23 nM。基于针对两个野生型激酶组（分别为375个和398个激酶）的分析研究，化合物对STK17A和STK17B均有强烈抑制作用，但仅对AAK1、MYLK4和NEK3/5有中等程度的脱靶抑制。此外，化合物具有良好的口服生物利用度，为针对各种癌症的体内研究铺平了道路。
