IDH enzyme inhibition in cancer therapy: mechanisms, mutational insights, and effects of IDH inhibitors in glioma, acute myeloid leukemia and chondrosarcoma.

Isocitrate dehydrogenase (IDH) enzymes have recently emerged as a highly promising target for therapeutic intervention in cancer treatment. Mutations in IDH genes result in the production of the oncometabolite, D-2-hydroxyglutarate (D-2HG), which contributes to tumorigenesis through epigenetic dysregulation, genomic methylation patterns and altered cellular metabolism. The functions of IDH1 and 2 under normal and cancer conditions are distinct from those of IDH3, although IDH1 and 2 are known to play a crucial role in cancer. IDH mutations are highly prevalent in various cancers such as gliomas, acute myeloid leukemia (AML) and chondrosarcoma. Thus, IDH inhibitors stand as a promising class of drugs in cancer treatments, by reducing tumor size and enhancing improvements in overall survival. In contrast, targeting specific IDH mutant with IDH inhibitors is associated with challenging and heterogenous outcome, as it causes resistance mechanisms such as isoform switching (From IDH 1-2 and vice versa), secondary mutations (D279N, S280F) and metabolic bypass, although these inhibitors are often well-tolerated with manageable side effects. On the other hand, wild type IDH itself acts as an oncogene when overexpressed, via, enhancing HIF1α signalling driven through Warburg effect, increasing tumor cell proliferation through prevention of oxidative stress response and inhibiting ferroptosis pathway, as reported in various cancers, including lung and breast cancer. Hence, this review emphasizes the biological functions of IDH enzymes, the impact of overexpressed wild type IDH levels and IDH mutations on cancer development and the recent therapeutic strategies, particularly targeting IDH for gliomas, AML and chondrosarcoma treatment. The potential of IDH inhibitors in personalized medicine approaches and their implications for improving patient outcomes, along with the computer-based emerging technologies such as Computer aided drug design, Machine learning and Artificial Intelligence tools for development of novel lead IDH inhibitors are also discussed.