2. Academic Validation
  3. 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

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

Affiliations

  • 1 AbbVie Incorporated, North Chicago, Illinois 60064, United States.
  • 2 AbbVie Bioresearch Center, Worcester, Massachusetts 01605, United States.
  • 3 X-Chem, Waltham, Massachusetts 02453, United States.
PMID: 38574366 DOI: 10.1021/acs.jmedchem.3c02397
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.

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