Oncrasin 1

Description

A cell-permeable indolecarboxaldehyde compound that selectively induces apoptosis in cells harboring mutant K-Ras both in vitro (IC₅₀ = 0.11, 0.25, 1.0, 1.58, and 4.81 µM in H2887, H460, H2122, A549, and T29Kt1 cultures, respectively) and in vivo (75% suppression of H460-derived tumor growth in mice; 100 mg/kg via daily i.p.), while exhibiting little or much reduced potency toward cells with wild-type Ras or mutant N-Ras (IC₅₀ ≥31 µM). Oncrasin-1 treatment is shown to induce PKC_ι aggregation with splicing factors in the nucleus and dissociation between PKC_ι and CDK9/Cyclin T1 in K-Ras mutant cultures, resulting in decreased RNA polymerase II phosphorylation and a suppression of RNA processing in general. Oncrasin-1-induced cell death requires the presence of both mutant K-Ras and PKC_ι, siRNA-mediated knockdown of either enzyme is demonstrated to abolish its cytotoxicity in H460 and T29Kt1 cultures. Proapoptotic agent that induces abnormal nuclear aggregation of PKC_ι and suppresses RNA transcription. Exhibits antiproliferative effects against various human tumor cell lines with K-Ras mutations (IC₅₀ ≤ 3 μM) with minimal effects on normal epithelial cells and inhibits human xenograft growth by 75% in vivo.