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

Abstract

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.

Horner–Wadsworth–Emmons reaction as an excellent tool in the synthesis of fluoro-containing biologically important compounds

“…These data are convincing that SPH5030 is a promising candidate for clinical-stage trials. 70 Amino acids are prone to racemization, that is why matching the most effective and suitable base for HWE olefination is very important. In the course of studies of numerous bases, 71 the best results were obtained using DBU (Masamune-Roush Scheme 13 Synthesis of the novel quinazoline analogues 67.…”

“…These data are convincing that SPH5030 is a promising candidate for clinical-stage trials. 70 In the Scheme 14 the synthesis of designed compounds 76 was shown. 2-(Diethoxyphosphoryl)-2-fluoroacetic acid 7′ with 72 in the presence of fosforyl chloride yielded the intermediate 73 .…”

“…The purpose of the studies presented by Xia and co-workers was the synthesis of new tyrosine kinase inhibitors (Scheme 14). 70 SPH5030 turned out to be a selective and irreversible HER2 inhibitor. It inhibits HER2WT and EGFRWT with IC 50 values of 3.51 and 8.13 nM, respectively.…”