The enzyme, isocitrate dehydrogenase (IDH) catalyzes the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate and CO2. It is found in the cytosol, mitochondrial matrix, and peroxisomes. IDH is responsible for cellular respiration in the TCA cycle. Isocitrate dehydrogenase exists in three isoforms including IDH1 (homodimeric enzyme which is primarily found in cytoplasm and peroxisomes), IDH2 (also a homodimeric enzyme located within the mitochondria) and IDH3 (a heterotetrameric enzyme found in the mitochondria).
Inhibitors of this enzyme are being developed as therapeutics targeting IDH mutation in cancers. Various studies conducted on these inhibitors have demonstrated that they are capable of binding to the alpha-ketoglutarate site and consequently act as binding competitors.
There is only one marketed product Idhifa, developed by Celgene which got approved in August 2017 by the USFDA. It is indicated for the treatment of patients with relapsed or refractory acute myeloid leukemia with an IDH2 mutation. The sale of Idhifa is estimated to reach USD 465.44 million by 2025.
The pipeline of IDH inhibitors is at a nascent stage with only a handful of IDH1 and IDH2 inhibitors under development. Agios Pharmaceuticals has emerged as a key player in the market which is developing two products, one in Phase III (late-stage) and the other in Phase I (early stage). These inhibitors mainly target oncology based indications including acute myeloid leukemia, hematologic malignancies, glioma, and chondrosarcomas.
There is a high unmet need for new therapies targeting this enzyme. Therefore, the promising therapeutic potential of mutant IDH inhibitors can pave the way for cancer treatment individualization to improve outcomes.