Pete I do not believe the Kevetrin story is over. Below is a study of a Kevetrin modification which reportedly increase its effectiveness 100X.Obvoiously more studies need to be done. Based of the results below I expect a whole series of studies based on these results.
In the present study, we designed and synthesized a novel analog (compound 900) of Kevetrin and its cytotoxicity was assessed using four different ovarian cancer cell lines viz. OVCAR-3, OVCAR-10, ES2, drug-resistant HeyA8 cells, and normal fibroblast cells (FHC). Compared to the control and Kevetrin, compound 900 inhibited the ovarian cancer cell viability in a dose- and time-dependent manner. The IC50 value of compound 900 was 0.8 µM, 0.7 µM, 0.8 µM, and 0.9 µM for OVCAR-3, HeyA8, OVCAR-10, and ES2 cells, respectively, while for Kevetrin the IC50 value was >100 µM for 48 h treatment. Compound 900 was thus found to be >100 times more potent than standard Kevetrin. To further acquaint the effect of 48 h treatment on cell proliferation, we performed trypan blue cell viability assay, trypan blue dye exclusion assay, Annexin V/7-AAD, Caspase 3/7 apoptosis assays, and Western blotting of apoptotic proteins involved in apoptosis. Compound 900 significantly induced apoptosis in OVCAR-3 and HeyA8 cells in a dose-dependent manner. Upregulation of several apoptotic proteins, as evident by Western blot, suggested that 900 causes the induction of apoptotic pathways efficiently. Further, the cell cycle analysis showed a significant arrest of OVCAR-3 and HeyA8 cells in the S-phase, which was further confirmed by the analysis of cyclin A2, cyclin-E1, p21, and p27 protein expression. Additionally, compound 900 caused a significant increase in the expression of the cell cycle inhibitory genes p21 and p27 in a p53-independent manner, compared to Kevetrin. Kevetrin has shown promise in preliminary clinical studies in solid tumor patients. The new analog 900 is >100 fold more potent than Kevetrin and holds great promise to be developed further for ovarian and other mechanistically relevant cancers.
Citation Format: Asif Raza, Jacek Krzeminski, Shantu Amin, Arun Sharma. Discovery of a novel Kevetrin analog as a potential therapeutic for ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1650.
