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

[Display omitted] •Development and optimization of a “Direct-to-Biology” workflow, with synthesis and biological evaluation in plate.•Introduction of structural diversity through SNAr to get analogues with good chemical purity and reliable biological data.•Fast evaluation of a variety of structurally diverse fragments leading to nanomolar SHP2 allosteric inhibitors. 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.