1. Discovery of Potent Azetidine-Benzoxazole MerTK Inhibitors with In Vivo Target Engagement.
- Author
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Frey RR, Jana N, Gorman JV, Wang J, Smith HA, Bromberg KD, Thakur A, Doktor SZ, Indulkar AS, Jakob CG, Upadhyay AK, Qiu W, Manaves V, Gambino F Jr, Valentino SA, Montgomery D, Zhou Y, Li T, Buchanan FG, Ferguson DC, Kurnick MD, Kapecki N, Lai A, Michaelides MR, and Penning TD
- Subjects
- Animals, Mice, Humans, Structure-Activity Relationship, Drug Discovery, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Cell Line, Tumor, Azetidines pharmacology, Azetidines chemistry, Azetidines pharmacokinetics, Azetidines chemical synthesis, Benzoxazoles pharmacology, Benzoxazoles chemistry, Benzoxazoles chemical synthesis, Benzoxazoles pharmacokinetics, c-Mer Tyrosine Kinase antagonists & inhibitors, c-Mer Tyrosine Kinase metabolism, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors chemical synthesis
- 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.
- Published
- 2024
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