The first clinical-stage SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase-2) inhibitor TNO155 was discovered by Novartis. The intriguing details of this discovery were documented in two consecutive papers, namely J. Med. Chem. 2016, 59, 7773−7782 and J. Med. Chem. 2020, 63, 13578−13594.
During a high-throughput screening process, a known ion channel inhibitor SHP836 was identified to exhibit inhibitory activity against the SHP2 enzyme in the micromolar range. Its binding mechanism to a channel-like allosteric site differed from the typical interaction mode of orthosteric inhibitors, which usually possess unfavorable physicochemical properties.
SHP836, which demonstrated improved drug-like properties, served as a solid starting point for development of the clinical trial candidate TNO155 through a promising compound SHP099. Although it had certain drawbacks, such as phototoxicity, vacuolation, and inhibition of hERG, SHP099 played a crucial role in the development process leading to the identification of TNO155. The chart below provides a comprehensive summary of the rigorous process of medicinal chemistry optimization conducted to identify TNO155.
