Discovery of MDV6058 (PF-06952229), a selective and potent TGFβR1 inhibitor: Design, synthesis and optimization. (1st November 2022)

• Record Type: Journal Article
• Authors: Pujala, Brahmam; Ramachandran, Sreekanth A.; Sonawane, Mukesh; Kamble, Maruti M.; Panpatil, Dayanand; Adhikari, Swati; Soni, Sanjeev; Subbareddy, Venkata; Shinde, Bharat U.; Nayak, Anjan K.; Bansal, Chandni; Gupta, Ashu; Mukherjee, Kakoli; Agarwal, Anil K.; Guerrero, Javier; Herrera, Francisco J.; Bernales, Sebastian; Guha, Mausumee; Chakravarty, Sarvajit; Pham, Son M.; Rai, Roopa
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 75(2022)
• Publication Date: 2022-11-01
• Subjects: TGFβR1 -- Cancer -- pSMAD2 -- ALK5 -- PF-06952229; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128979
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Compound 1 is a potent TGF-β receptor type-1 (TGFβR1 or ALK5) inhibitor but is metabolically unstable. A solvent-exposed part of this molecule was used to analogue and modulate cell activity, liver microsome stability and mouse pharmacokinetics. The evolution of SAR that led to the selection of 2 (MDV6058 / PF-06952229) as a preclinical lead compound is described.