5QU0 | pdb_00005qu0

Discovery of BMS-986260, a Potent, Selective, and Orally Bioavailable TGF beta R1 Inhibitor as an Immuno-oncology Agent.

Velaparthi, U., Darne, C.P., Warrier, J., Liu, P., Rahaman, H., Augustine-Rauch, K., Parrish, K., Yang, Z., Swanson, J., Brown, J., Dhar, G., Anandam, A., Holenarsipur, V.K., Palanisamy, K., Wautlet, B.S., Fereshteh, M.P., Lippy, J., Tebben, A.J., Sheriff, S., Ruzanov, M., Yan, C., Gupta, A., Gupta, A.K., Vetrichelvan, M., Mathur, A., Gelman, M., Singh, R., Kinsella, T., Murtaza, A., Fargnoli, J., Vite, G., Borzilleri, R.M.

(2020) ACS Med Chem Lett 11: 172-178

• PubMed: 32071685 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1021/acsmedchemlett.9b00552
• Primary Citation of Related Structures:  
  5QTZ, 5QU0


• PubMed Abstract: 
  

  Novel imidazole-based TGFβR1 inhibitors were identified and optimized for potency, selectivity, and pharmacokinetic and physicochemical characteristics. Herein, we report the discovery, optimization, and evaluation of a potent, selective, and orally bioavailable TGFβR1 inhibitor, 10 (BMS-986260). This compound demonstrated functional activity in multiple TGFβ-dependent cellular assays, excellent kinome selectivity, favorable pharmacokinetic properties, and curative in vivo efficacy in combination with anti-PD-1 antibody in murine colorectal cancer (CRC) models. Since daily dosing of TGFβR1 inhibitors is known to cause class-based cardiovascular (CV) toxicities in preclinical species, a dosing holiday schedule in the anti-PD-1 combination efficacy studies was explored. An intermittent dosing regimen of 3 days on and 4 days off allowed mitigation of CV toxicities in one month dog and rat toxicology studies and also provided similar efficacy as once daily dosing.

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Organizational Affiliation: 

Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.