2. Academic Validation
  3. Potent, Selective, and Orally Bioavailable Quinazoline-Based STK17A/B Dual Inhibitors

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.
Sana Chaudhry 1,  Jesus R Castro 1,  Tulasigeri M Totiger 1,  Jumana Afaghani 1,  Rabia Khurshid 2,  Miah Nicholls 1,  Ziming Zhang 3,  Stephan C Schürer 1 2,  Ashish Shah 1,  Justin Taylor 1,  Yangbo Feng 1 2
Affiliations

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 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.

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