Kevetrin

Kevetrin (3-Cyanopropyl carbamimidothioate; 4-Isothioureidobutyronitrile) is an apoptosis inducer that exhibits both p53-dependent and p53-independent anti-tumor activity. In TP53 wild-type models, Kevetrin activates and stabilizes the p53 protein by altering the processing of MDM2, leading to cell cycle arrest and apoptosis. It shows increased sensitivity in mutant models. Kevetrin is applicable for research in various cancers, including acute myeloid leukemia and breast cancer.

Kevetrin (85-340 μM; 6-72 h) does not affect cell viability or induce significant apoptosis in TP53 wild-type MOLM-13 acute myeloid leukemia (AML) cells. However, it reduces cell viability and induces apoptosis in TP53 mutant KASUMI-1 AML cells in a dose- and time-dependent manner, with enhanced efficacy noted after repeated dosing cycles. At 340 μM for 6 hours, Kevetrin alters the expression of MT family genes and some leukemia-related transcription factors in both TP53 wild-type MOLM-13 cells and TP53 mutant KASUMI-1 AML cells. Exposure to Kevetrin (85-340 μM; 48 h) decreases cell viability in both TP53 wild-type and mutant AML cell lines, with mutant lines displaying greater sensitivity. Moreover, at 85-340 μM for 24-48 hours, Kevetrin induces apoptosis in both types of cell lines, with the mutant lines showing a stronger dose-dependent apoptotic response. In TP53 wild-type OCI-AML3 cells and TP53 mutant NOMO-1 AML cells, Kevetrin (85, 170, 340 μM; 24-48 h) induces G0/G1 cell cycle arrest, but does not alter the cell cycle in TP53 wild-type MOLM-13 cells or TP53 mutant KASUMI-1 AML cells. It decreases viability and induces apoptosis in primary AML cells, displaying selective cytotoxic activity towards blasts, and shows heightened sensitivity in TP53 mutant primary samples. Kevetrin (340 μM; 48 h) modifies common core transcriptional programs in both TP53 wild-type MOLM-13 and TP53 mutant KASUMI-1 AML cells, downregulating key oncogenic pathways such as glycolysis and DNA repair, while upregulating p53 target genes and p53 pathway-related transcriptional features. It also upregulates the expression of p21 in TP53 wild-type AML cells in a dose-dependent fashion, enhances p53 expression levels and its nuclear localization, and promotes the accumulation of p53 in apoptotic cells, with a stronger induction effect in TP53 mutant AML cell lines.