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

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 in patients. The development
of HER2 mutation during treatment also hampers the progress of the
treatment. We used a molecular hybridization strategy for structural
optimizations, in conjunction with in vitro and in vivo drug-like property screening, to obtain a clinical
candidate SPH5030. Overall, SPH5030 showed
excellent activities against four frequent kinds of HER2 mutants and
high relative HER2 selectivity compared with neratinib and pyrotinib,
good pharmacokinetic characteristics with desirable bioavailabilities,
and significant in vivo antitumor efficacy in xenograft
mouse models, especially in a HER2 mutation A775_G776insYVMA xenograft
mouse model with its potency much higher than those of neratinib and
pyrotinib.