Discovery of novel natural-product-derived mutant isocitrate dehydrogenases 1 inhibitors: Structure-based virtual screening, biological evaluation and structure-activity relationship study.

Mutations in IDH1 are commonly observed across various cancers, causing the conversion of α-KG to 2-HG. Elevated levels of 2-HG disrupt histone and DNA demethylation processes, promoting tumor development. Consequently, there is substantial interest in developing small molecule inhibitors targeting the mutant enzymes. Herein, we report a structure-based high-throughput virtual screening strategy using a natural products library, followed by hit-to-lead optimization. Through this process, we discover a potent compound, named 11s, which exhibited significant inhibition to IDH1 R132H and IDH1 R132C with IC50 values of 124.4 and 95.7 nM, respectively. Furthermore, 11s effectively reduced 2-HG formation, with EC50 values of 182 nM in U87 R132H cell, and 84 nM in HT-1080 cell. In addition, 11s significantly reduced U87 R132H and HT-1080 cell proliferation with GC50 values of 3.48 and 1.38 µM, respectively. PK-PD experiments further confirmed that compound 11s significantly decreased 2-HG formation in an HT-1080 xenograft mouse model, resulting in notable suppression of tumor growth without apparent loss in body weight.

Discovery of novel Thymol-TPP antibiotics that eradicate MRSA persisters.

The high prevalence of methicillin-resistant Staphylococcus aureus (MRSA) strains and the formation of non-growing, dormant "persisters" subsets help bacteria evade antibiotic treatment and enhance bacterial resistance, which poses a serious threat to human life and health. It is urgent to discover novel antibacterial therapies effective against MRSA persisters. Thymol is a common nutraceutical with weak antibacterial and antitumor activities. A series of Thymol triphenylphosphine (TPP) conjugates (TPP-Thy3) was designed and synthesized. These compounds showed significantly improved inhibitory activity against Gram-positive bacteria compared with Thymol. Among them, Thy3d displayed a low probability of resistance selection and showed excellent biocompatibility. Interestingly, Thy3d elicited a rapid killing effect of MRSA persisters (99.999%) at high concentration. Fluorescence experiments, electron microscopy, molecular dynamics simulation and bilayer experiment confirmed that Thy3d conjugates exerted potent antimicrobial activity by disrupting the integrity of the membrane of bacterial even the persister. Furthermore, Thy3d exhibited considerable efficacy in a mouse model of subcutaneous murine MRSA infection. In summary, TPP-Thy3 conjugates are a series of novel antibacterial agents and could serve as a new therapeutic strategy for combating antibiotic resistance.