2. Academic Validation
  3. Direct-to-biology platform: From synthesis to biological evaluation of SHP2 allosteric inhibitors

Direct-to-biology platform: From synthesis to biological evaluation of SHP2 allosteric inhibitors

  • Bioorg Med Chem Lett. 2024 Mar 1:100:129626. doi: 10.1016/j.bmcl.2024.129626.
Simona Ponzi 1,  Federica Ferrigno 2,  Monica Bisbocci 3,  Cristina Alli 3,  Jesus M Ontoria 2,  Alessia Petrocchi 2,  Carlo Toniatti 4,  Esther Torrente 2
Affiliations

Affiliations

  • 1 Department of Drug Discovery, IRBM S.p.A., Via Pontina km 30.600, 00071 Pomezia, Rome, Italy. Electronic address: s.ponzi@irbm.com.
  • 2 Department of Drug Discovery, IRBM S.p.A., Via Pontina km 30.600, 00071 Pomezia, Rome, Italy.
  • 3 Department of Biology and Translational Research, IRBM S.p.A., Via Pontina km 30.600, 00071 Pomezia, Rome, Italy.
  • 4 Chief Scientific Officer, IRBM S.p.A., Via Pontina km 30.600, 00071 Pomezia, Rome, Italy.
PMID: 38266789 DOI: 10.1016/j.bmcl.2024.129626
Abstract

Tyrosine Phosphatase SHP2 is a proto-oncogenic protein involved in cell growth and differentiation via diverse intracellular signaling pathways. With the scope of identifying new SHP2 allosteric inhibitors, we report here the development and optimization of a high-throughput "Direct-to-Biology" (D2B) workflow including the synthesis and the biological evaluation of the reaction crude, thus eliminating the need for purification. During this labor-saving procedure, the structural diversity was introduced through a SNAr reaction. A wide array of analogues with good chemical purity was generated, allowing the obtention of reliable biological data which validated this efficient technique. This approach enabled the fast evaluation of a variety of structurally diverse fragments leading to nanomolar SHP2 allosteric inhibitors and a new series bearing a novel bicyclo[3.1.0]hexane moiety.

Keywords

Allosteric inhibitors; Chemistry in plate; Direct-to-Biology; Imidazopyrazines; Oncology; SHP2.

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