In response to Novartis’ publication of TNO155, the Institute for Applied Cancer Science (IACS) at the University of Texas MD Anderson Cancer Center made a significant scientific contribution by unveiling their SHP2 inhibitor, designated as IACS-15414. By employing in silico screening techniques, they utilized the crystal structure of the SHP2 mutant T468 protein (4OHL) as a model, leading to the identification of a pyrrolopyrimidinone scaffold. Despite encountering challenges such as low permeability and high efflux ratio in the analogues derived from this scaffold, an in-depth comprehension of the protein’s structure empowered the discovery chemists to substitute the previous scaffold with pyrrolopyrimidine and subsequently pyrimidone, ultimately resulting in the optimal SHP2 inhibitor candidate, ICAS-15414. While this published account may not encompass the entirety of the underlying process, it successfully exemplifies the fundamental principles of structure-based drug design. However, this SHP2 inhibitor did not undergo clinical trials; instead, a different compound called IACS-15509 (BBP-398) was chosen for use. (J. Med. Chem. 2021, 64, 15141−15169)
