Potent, Selective, and Orally Bioavailable Quinazoline-Based STK17A/B Dual Inhibitors

Sana Chaudhry; Jesus R Castro; Tulasigeri M Totiger; Jumana Afaghani; Rabia Khurshid; Miah Nicholls; Ziming Zhang; Stephan C Schürer; Ashish Shah; Justin Taylor; Yangbo Feng

doi:10.1021/acsmedchemlett.4c00125

Potent, Selective, and Orally Bioavailable Quinazoline-Based STK17A/B Dual Inhibitors

ACS Med Chem Lett. 2024 May 20;15(6):945-949. doi: 10.1021/acsmedchemlett.4c00125. eCollection 2024 Jun 13.

Authors

Affiliations

¹ Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida33136, United States.
² Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida 33136, United States.
³ Department of Chemistry, University of Miami, Miami, Florida 33146, United State.

PMID: 38894933
PMCID: PMC11181493 (available on 2025-06-13)
DOI: 10.1021/acsmedchemlett.4c00125

Abstract

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 9 had an STK17A inhibitory IC₅₀ of 23 nM. Based on profiling studies against two wild-type kinase panels (375 and 398 kinases, respectively), compound 9 had strong inhibition of both STK17A and STK17B but moderate off-target inhibition only for AAK1, MYLK4, and NEK3/5. In addition, compound 9 had good oral bioavailability, paving the way for in vivo studies against various cancers.