Simona Ponzi, Federica Ferrigno, Monica Bisbocci, Cristina Alli, Jesus M. Ontoria, Alessia Petrocchi, Carlo Toniatti, Esther Torrente, Direct-to-biology platform: From synthesis to biological evaluation of SHP2 allosteric inhibitors, Bioorganic & Medicinal Chemistry Letters, Volume 100, 2024
Highlights
- Development and optimization of a high-throughput “Direct-to-Biology” (D2B) workflow for integrated synthesis and biological evaluation.
- Introduction of structural diversity through SNAr reactions, generating analogues with excellent chemical purity and robust biological data.
- Rapid evaluation of diverse fragments, resulting in nanomolar SHP2 allosteric inhibitors.
Graphical Abstract
Abstract
The tyrosine phosphatase SHP2 is a proto-oncogenic protein that plays a critical role in cell growth, differentiation, and intracellular signal transduction pathways. To identify novel SHP2 allosteric inhibitors, we developed and optimized an innovative high-throughput “Direct-to-Biology” (D2B) workflow. This process integrates synthesis and biological evaluation directly from reaction mixtures, bypassing the need for purification. By employing SNAr reactions, we introduced significant structural diversity, resulting in a broad library of analogues with high chemical purity and reproducible biological activity.
This streamlined approach facilitated the rapid screening of structurally diverse fragments, leading to the discovery of nanomolar SHP2 inhibitors. Among these, a novel series featuring a bicyclo[3.1.0]hexane moiety was identified, offering new opportunities for further optimization. This efficient and scalable technique underscores its value for accelerating the development of innovative inhibitors targeting SHP2.
