2. Academic Validation
  3. Discovery of Potent Azetidine-Benzoxazole MerTK Inhibitors with In Vivo Target Engagement

Discovery of Potent Azetidine-Benzoxazole MerTK Inhibitors with In Vivo Target Engagement

  • J Med Chem. 2024 Oct 10;67(19):17033-17052. doi: 10.1021/acs.jmedchem.4c01451.
Robin R Frey 1,  Navendu Jana 1,  Jacob V Gorman 1,  Jin Wang 1,  Heath A Smith 1,  Kenneth D Bromberg 1,  Ashish Thakur 1,  Stella Z Doktor 1,  Anura S Indulkar 1,  Clarissa G Jakob 1,  Anup K Upadhyay 1,  Wei Qiu 1,  Vlasios Manaves 1,  Frank Gambino Jr 1,  Stephen A Valentino 1,  Debra Montgomery 1,  Yebin Zhou 1,  Tao Li 1,  Fritz G Buchanan 1,  Debra C Ferguson 1,  Matthew D Kurnick 1,  Nicolas Kapecki 1,  Albert Lai 1,  Michael R Michaelides 1,  Thomas D Penning 1
Affiliations

Affiliation

  • 1 Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
PMID: 39350472 DOI: 10.1021/acs.jmedchem.4c01451
Abstract

Inhibition of the receptor tyrosine kinase MerTK by small molecules has the potential to augment the immune response to tumors. Potent, selective inhibitors with high levels of in vivo target engagement are needed to fully evaluate the potential use of MerTK inhibitors as Cancer therapeutics. We report the discovery and optimization of a series of pyrazinamide-based type 1.5 MerTK inhibitors bearing an azetidine-benzoxazole substituent. Compound 31 potently engages the target in vivo and demonstrates single agent activity in the immune-driven MC-38 murine syngeneic tumor model.

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