Discovery of MDV6058 (PF-06952229), a selective and potent TGFβR1 inhibitor: Design, synthesis and optimization

Brahmam Pujala; Sreekanth A Ramachandran; Mukesh Sonawane; Maruti M Kamble; Dayanand Panpatil; Swati Adhikari; Sanjeev Soni; Venkata Subbareddy; Bharat U Shinde; Anjan K Nayak; Chandni Bansal; Ashu Gupta; Kakoli Mukherjee; Anil K Agarwal; Javier Guerrero; Francisco J Herrera; Sebastian Bernales; Mausumee Guha; Sarvajit Chakravarty; Son M Pham; Roopa Rai

doi:10.1016/j.bmcl.2022.128979

Discovery of MDV6058 (PF-06952229), a selective and potent TGFβR1 inhibitor: Design, synthesis and optimization

Bioorg Med Chem Lett. 2022 Nov 1:75:128979. doi: 10.1016/j.bmcl.2022.128979. Epub 2022 Sep 8.

Authors

Brahmam Pujala¹, Sreekanth A Ramachandran¹, Mukesh Sonawane¹, Maruti M Kamble¹, Dayanand Panpatil¹, Swati Adhikari¹, Sanjeev Soni¹, Venkata Subbareddy¹, Bharat U Shinde¹, Anjan K Nayak¹, Chandni Bansal¹, Ashu Gupta¹, Kakoli Mukherjee¹, Anil K Agarwal¹, Javier Guerrero², Francisco J Herrera³, Sebastian Bernales³, Mausumee Guha⁴, Sarvajit Chakravarty³, Son M Pham³, Roopa Rai⁵

Affiliations

¹ Integral BioSciences Pvt. Ltd., C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
² Fundación Ciencia & Vida, Avenida Zañartu 1482, Ñuñoa, Santiago, 778027, Chile.
³ Medivation, Inc., 525 Market Street, 36(th) Floor, San Francisco, CA 94105, USA.
⁴ Medivation, Inc., 525 Market Street, 36(th) Floor, San Francisco, CA 94105, USA; Pfizer Inc., Pfizer World Wide Research & Development, Building CB-4, 10777 Science Center Dr. La Jolla, CA 92121-1111, USA.
⁵ Medivation, Inc., 525 Market Street, 36(th) Floor, San Francisco, CA 94105, USA. Electronic address: [email protected].

PMID: 36089110
DOI: 10.1016/j.bmcl.2022.128979

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.

Keywords: ALK5; Cancer; PF-06952229; TGFβR1; pSMAD2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Mice
Receptors, Transforming Growth Factor beta*
Solvents

Substances

Receptors, Transforming Growth Factor beta
Solvents