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.

Improving the positional adaptability: structure-based design of biphenyl-substituted diaryltriazines as novel non-nucleoside HIV-1 reverse transcriptase inhibitors.

In order to improve the positional adaptability of our previously reported naphthyl diaryltriazines (NP-DATAs), synthesis of a series of novel biphenyl-substituted diaryltriazines (BP-DATAs) with a flexible side chain attached at the C-6 position is presented. These compounds exhibited excellent potency against wild-type (WT) HIV-1 with EC50 values ranging from 2.6 to 39 nmol/L and most of them showed low nanomolar anti-viral potency against a panel of HIV-1 mutant strains. Compounds 5j and 6k had the best activity against WT, single and double HIV-1 mutants and reverse transcriptase (RT) enzyme comparable to two reference drugs (EFV and ETR) and our lead compound NP-DATA (1). Molecular modeling disclosed that the side chain at the C-6 position of DATAs occupied the entrance channel of the HIV-1 reverse transcriptase non-nucleoside binding pocket (NNIBP) attributing to the improved activity. The preliminary structure-activity relationship and PK profiles were also discussed.

Synthesis and biological evaluation of dihydroquinazoline-2-amines as potent non-nucleoside reverse transcriptase inhibitors of wild-type and mutant HIV-1 strains.

A novel series of dihydroquinazolin-2-amine derivatives were synthesized and evaluated for their anti-HIV-1 activity in MT-4 cell cultures. All of the molecules were active against wild-type HIV-1 with EC50 values ranging from 0.61 µM to 0.84 nM. The most potent inhibitor, compound 4b, had an EC50 value of 0.84 nM against HIV-1 strain IIIB, and thus was more active than the reference drugs efavirenz and etravirine. Moreover, most of the compounds maintained high activity (low-micromolar EC50 values) against strains bearing the reverse transcriptase (RT) E138K mutation. Compound 4b had EC50 values of 3.5 nM and 66 nM against non-nucleoside reverse transcriptase inhibitor-resistant strains bearing the RT E138K and RES056 mutations. In enzyme activity assays, compound 4b exhibited an IC50 value of 10 nM against HIV-1 RT. Preliminary SARs and molecular docking studies provide valuable insights for further optimization.

Design and synthesis of a novel series of non-nucleoside HIV-1 inhibitors bearing pyrimidine and N-substituted aromatic piperazine.

A novel series of substituted piperazine-1-yl-pyrimidine derivatives were designed and synthesized as a new type of HIV-1 non-nucleoside inhibitors. Various N-substituted aromatic groups were incorporated into the piperazine ring through a simple and practical route to investigate the biological activity of these target compounds against wild-type and resistant strains of HIV-1. All of the target compounds were also evaluated as HIV-1 reverse transcriptase inhibitors in MT-4 cell cultures. The biological results showed that six of these compounds displayed inhibitory activities against the wild-type strain, among of which 7q and 7t were found to be the two most active analogues possessing EC50 values of 31.50 µM and 3.36 µM, respectively. Molecular modeling studies of 7q provide valuable information for developing new anti-HIV-1 inhibitors.

Discovery of biphenyl-substituted diarylpyrimidines as non-nucleoside reverse transcriptase inhibitors with high potency against wild-type and mutant HIV-1.

A novel series of diarylpyrimidine (DAPY) derivatives bearing the biphenyl motif with multiple substituted groups was synthesized as human immunodeficiency virus (HIV)-1 non-nucleoside reverse transcriptase inhibitors. All of the target compounds were evaluated for their in vitro activity against HIV in MT-4 cells. Most of the compounds exhibited excellent activity with low nanomolar EC50 values against wild-type, single and double mutant HIV-1 strains. Compound 4b displayed an EC50 value of 1 nM against HIV-1 IIIB, 1.3 nM against L100I, 0.84 nM against K103 N, 1.5 nM against Y181C, 11 nM against Y188L, 2 nM against E138K, 10 nM against K103 N + Y181C, and almost 110 nM against F227L + V106. The improvement in the selectivity and potency of the target molecules against the wild-type and mutant HIV-1 strains validated our hypothesis. The biphenyl ring in the DAPY derivatives could strengthen the π-π stacking effect between the target molecule and the non-nucleoside inhibitor-binding pocket in the reverse transcriptase by extending the conjugating systems. This research represented a significant step toward the discovery of novel therapeutic DAPYs for treating acquired immunodeficiency syndrome in patients infected with HIV-1.