Development of active site directed inhibitors and bifunctional degraders of isocitrate dehydrogenase mutants

About This Grant

Abstract: Dysfunction in essential metabolic enzymes drives human cancers. Within this dysfunction, heterozygous mutations in genes encoding isocitrate dehydrogenases IDH1 and IDH2 are frequent in both progressive gliomas and hematological malignancies and contribute to the development of specific tumor subtypes. These mutations, specifically at conserved arginine residues, impair NADP+-dependent oxidative decarboxylation of isocitrate to 2-oxoglutarate (2OG), and adopt a cryptic ketoreductase activity to produce (R)- 2-hydroxyglutarate (2HG) from 2OG using NADPH as the reductant. 2HG is an oncometabolite known to induce tumorigenesis by impairing differentiation and immune surveillance, causing expansion of progenitor cells and enhanced proliferation. How the distinct biochemical features of each mutant contribute to the development of specific tumor subtypes is not well understood. Medicinal chemistry efforts have led to FDA-approved allosteric inhibitors of IDH 1 and 2 mutants, ivosidenib and enasidenib, respectively. However, acquired resistance to such targeted therapy has recently emerged in cancer patients carrying these IDH mutations and no treatment modality is currently available to target the resistant mutants. To circumvent such challenges, we propose a significant departure from the allosteric modulators currently used in clinic, instead developing active site directed inhibitors to interrogate specific IDH mutants and cancer subtypes. Once developed, evolving the inhibitors into active site directed proteolysis targeting chimeras (PROTACs) will enable proteasomal degradation of the resistant mutants in cancer cells. By employing a class of compounds with chemotypes complementary to the distinct stereoelectronic features of IDH mutants, we illustrate both the promise and feasibility of development of such subtype-selective inhibitors and degraders. We will undertake systematic chemical, biochemical, structural and proteomic studies to develop potent and specific inhibitors and PROATCs with activity against IDH variants while characterizing the molecular changes that induce differentiation and halt proliferation of patient-derived cancer cells. The proposed reagents are anticipated to have broad biomedical significance both as chemical probes for gaining mechanistic insights as well as therapeutic prototypes to establish efficacy in animal models, catalyze early lead discovery, and foster clinical trials to develop next-generation oncology drugs.