Discovery of Small Molecule Interleukin 17A Inhibitors with Novel Binding Mode and Stoichiometry: Optimization of DNA-Encoded Chemical Library Hits to In Vivo Active Compounds PMID: 38574366

ADC Targets in Oncology

2026-04-10

Discovery of Small Molecule Interleukin 17A Inhibitors with Novel Binding Mode and Stoichiometry: Optimization of DNA-Encoded Chemical Library Hits to In Vivo Active Compounds

J Med Chem. 2024 Apr 4. doi: 10.1021/acs.jmedchem.3c02397.

Ashley L Ramos ¹ , Eric R Goedken ² , Kristine E Frank ¹ , Maria A Argiriadi ² , Sana Bazzaz ³ , Zhiguo Bian ¹ , Jesse T C Brown ¹ , Paolo A Centrella ³ , Hui-Ju Chen ¹ , Jeremy S Disch ³ , Pamela L Donner ¹ , David B Duignan ² , Diana Gikunju ³ , Stephen N Greszler ¹ , Marie-Aude Guié ³ , Sevan Habeshian ³ , Hajnalka E Hartl ³ , Christopher D Hein ¹ , Charles W Hutchins ¹ , Rachael Jetson ³ , Anthony D Keefe ³ , Hasan Khan ¹ , Huan-Qiu Li ¹ , Allison Olszewski ³ , Benjamin J Ortiz Cardona ¹ , Augustine Osuma ¹ , Sanjay C Panchal ¹ , Ryan Phelan ¹ , Wei Qiu ¹ , J Brad Shotwell ¹ , Anurupa Shrestha ¹ , Myron Srikumaran ¹ , Zhi Su ¹ , Chaohong Sun ¹ , Anup K Upadhyay ¹ , Michael D Wood ¹ , Haihong Wu ¹ , Ruijie Zhang ¹ , Ying Zhang ³ , Gang Zhao ¹ , Haizhong Zhu ¹ , Matthew P Webster ¹

Affiliations

Abstract

Dysregulation of IL17A drives numerous inflammatory and autoimmune disorders with inhibition of IL17A using antibodies proven as an effective treatment. Oral anti-IL17 therapies are an attractive alternative option, and several preclinical small molecule IL17 inhibitors have previously been described. Herein, we report the discovery of a novel class of small molecule IL17A inhibitors, identified via a DNA-encoded chemical library screen, and their subsequent optimization to provide in vivo efficacious inhibitors. These new protein-protein interaction (PPI) inhibitors bind in a previously undescribed mode in the IL17A protein with two copies binding symmetrically to the central cavities of the IL17A homodimer.