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
  • 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.

Products