Discovery of Pyrazole-Containing RGD Mimics with Anti-Fibrotic Efficacy in the Unilateral Ureteral Obstruction Mouse Model PMID: 42593930

ADC Targets in Oncology

2026-04-10

Discovery of Pyrazole-Containing RGD Mimics with Anti-Fibrotic Efficacy in the Unilateral Ureteral Obstruction Mouse Model

J Med Chem. 2026 Aug 13;69(15):18099-18116. doi: 10.1021/acs.jmedchem.6c00371.

Guohua Zhao ¹ , James John Mignone ¹ , Leatte Guernon ¹ , Eric Mull ¹ , Swanee Jacutin-Porte ¹ , Yuan Tian ¹ , Wei Wang ¹ , Xiaojun Han ¹ , Palani Kumar Balasubramanian ² , Suresh Dhanusu ² , Selvakumar Kumaravel ² , Srinath Subramaniam ² , Manoranjan Panda ² , Yan Shi ¹ , Bei Wang ¹ , Dawn Sun ¹ , Dauh-Rurng Wu ¹ , Rulin Zhao ¹ , Yi-Xin Li ¹ , Arvind Mathur ¹ , Brad Maxwell ¹ , Susan Pieniazek ¹ , Hyunsoo Park ¹ , Jodi K Muckelbauer ¹ , Dipal Patel ¹ , Theresa Ziemba ¹ , Christian Caporuscio ¹ , Kimberly A Foster ¹ , Evan B Janovitz ¹ , Zhengping Ma ¹ , Pitchumani Sivakumar ¹ , Ruihua Chen ¹ , Mary Ellen Cvijic ¹ , Jing Wang ¹ , Joseph R Taylor ¹ , Chris Freeden ¹ , Bradley Zinker ¹ , David A Gordon ¹ , Bruce Ellsworth ¹ , Jeffrey Robl ¹ , Joanne J Bronson ¹ , Dong Cheng ¹ , Pratik Devasthale ¹

Affiliations

Abstract

Fibrotic diseases such as idiopathic pulmonary fibrosis (IPF), metabolic dysfunction-associated steatohepatitis (MASH), and kidney fibrosis represent a major unmet medical need. IPF patients have a mean survival of only 2-5 years, and despite this critical need, only two drugs have been approved in the past decade. These therapies offer limited efficacy and poor tolerability, underscoring the need for better options. Targeting αV integrins has emerged as a promising strategy, supported by strong preclinical data. While αvβ1/6 inhibitors are in clinical trials, our approach focused on developing pan-αV inhibitors with selectivity over αvβ8 and αIIbβ3 and oral pharmacokinetics. Through lead optimization, we identified compound 14, a potent inhibitor of αvβ1, αvβ3, αvβ5, and αvβ6, with high selectivity, oral bioavailability, and low IV clearance. In a mouse unilateral ureteral obstruction model, oral dosing of 14 (10 mg/kg/day for 8 days) reduced total Collagen by 25% versus vehicle.