Ligandability Assessment of IL-1β by Integrated Hit Identification Approaches

  • J Med Chem. 2024 May 23;67(10):8141-8160. doi: 10.1021/acs.jmedchem.4c00240.
Anna Vulpetti  1 ,  Jean-Michel Rondeau  1 ,  Marie-Hélène Bellance  1 ,  Jutta Blank  1 ,  Ralf Boesch  1 ,  Andreas Boettcher  1 ,  Frédéric Bornancin  1 ,  Sylvia Buhr  1 ,  Lauren E Connor  1 ,  Christoph E Dumelin  1 ,  Oliver Esser  1 ,  Michael Hediger  1 ,  Samuel Hintermann  1 ,  Ulrich Hommel  1 ,  Elke Koch  1 ,  Guillaume Lapointe  1 ,  Lukas Leder  1 ,  Sylvie Lehmann  1 ,  Philipp Lehr  1 ,  Peter Meier  1 ,  Lionel Muller  1 ,  Daniela Ostermeier  1 ,  Paul Ramage  1 ,  Sihame Schiebel-Haddad  1 ,  Alexander Baxter Smith  1 ,  Aleksandar Stojanovic  1 ,  Juraj Velcicky  1 ,  Rina Yamamoto  1 ,  Konstanze Hurth  1
Affiliations
  • 1. Biomedical Research, Novartis, CH-4002 Basel, Switzerland.
PMID: 38728572 DOI: 10.1021/acs.jmedchem.4c00240
Abstract

Human interleukin-1β (IL-1β) is a pro-inflammatory cytokine that plays a critical role in the regulation of the immune response and the development of various inflammatory diseases. In this publication, we disclose our efforts toward the discovery of IL-1β Binders that interfere with IL-1β signaling. To this end, several technologies were used in parallel, including fragment-based screening (FBS), DNA-encoded library (DEL) technology, peptide discovery platform (PDP), and virtual screening. The utilization of distinct technologies resulted in the identification of new chemical entities exploiting three different sites on IL-1β, all of them also inhibiting the interaction with the IL-1R1 receptor. Moreover, we identified lysine 103 of IL-1β as a target residue suitable for the development of covalent, low-molecular-weight IL-1β antagonists.

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