AGI-6780

Targeting IDH2 with shRNA or its inhibitor AGI-6780 caused an increase in intracellular α-ketoglutarate concentration and a decrease in ATP and SAM levels, leading to a reduction in the methylation of STING promoter and elevated levels expression of STING. The increase of STING expression underlies the activation of type I interferon pathway observed in IDH2 compromised tumor cells and increased defense responses in the tumors in mice. These results identify IDH2 as a potential target to enhance cancer immune therapy.

Pan-cancer samples suggested that high RHEBL1 expression facilitates TAM infiltration and is correlated with tumour immunosuppressive status (TCGA). High expression of RHEBL1 may benefit from the therapy of 5-FU, ABT737, Afuresertib, AGI-5198, AGI-6780, and Alisertib.

We also identified selective inhibitors for ccRCC with PBRM1 mutation using online databases such as PD173074 and AGI-6780...Although PBRM1 mutation did not show an association with ccRCC prognosis, a lower PBRM1 expression level correlated with worsened prognosis. Our study provides insights into the association of PBRM1 mutation with disease progression in ccRCC and suggests potential gene and signaling pathways for personalized treatment in ccRCC with PBRM1 mutation.

To understand the underlying resistance mechanisms in response to imatinib (IMA) and adriamycin (ADR), the parental K562 cells were treated with low doses of IMA or ADR for two months to generate derivative cells with mild, intermediate and severe resistance to the drugs as defined by their increasing resistance index (RI). In particular, IDH2 was identified as a potential drug target correlated with the drug resistance phenotype, and its inhibition by the antagonist AGI-6780 reversed the acquired resistance in K562 cells to either ADR or IMA. Together, our study has implicated IDH2 as a potential target that can be therapeutically leveraged to alleviate the drug resistance in K562 cells when treated with IMA and ADR.

These results indicate that CP-17 can serve as a lead compound for the development of inhibitory drugs against AML with IDH2/R140Q mutant. Video abstract.