Discovery of SPH5030, a Selective, Potent, and Irreversible Tyrosine Kinase Inhibitor for HER2-Amplified and HER2-Mutant Cancer Treatment br

Small-molecule irreversible tyrosine kinase inhibitors as high potent agents have led to improvements in disease-free and overall survival in patients with HER2-amplified cancer. The approved irreversible HER2 inhibitors, neratinib and pyrotinib,both lack HER2 selectivity, leading to off-target adverse events inpatients. The development of HER2 mutation during treatmentalso hampers the progress of the treatment. We used a molecularhybridization strategy for structural optimizations, in conjunctionwithin vitroandin vivodrug-like property screening, to obtain aclinical candidateSPH5030. Overall,SPH5030showed excellentactivities against four frequent kinds of HER2 mutants and highrelative HER2 selectivity compared with neratinib and pyrotinib, good pharmacokinetic characteristics with desirablebioavailabilities, and significantin vivoantitumor efficacy in xenograft mouse models, especially in a HER2 mutationA775_G776insYVMA xenograft mouse model with its potency much higher than those of neratinib and pyrotinib.