OT-82, a novel anticancer drug candidate that targets the strong dependence of hematological malignancies on NAD biosynthesis
Effective management of some kinds of cancer is possible by modulating cell lineage-specific instead of tumor-specific targets. We conducted an organized look for novel agents selectively toxic to cells of hematopoietic origin. Chemical library screenings adopted by hit-to-lead optimization identified OT-82, a little molecule with strong effectiveness against hematopoietic malignancies including acute myeloblastic and lymphoblastic adult and pediatric leukemias, erythroleukemia, multiple myeloma, and Burkitt’s lymphoma in vitro as well as in mouse xenograft models. OT-82 seemed to be more toxic towards patients-derived leukemic cells versus healthy bone marrow-derived hematopoietic precursors. OT-82 was proven to induce cell dying by inhibiting nicotinamide phosphoribosyltransferase (NAMPT), the speed-restricting enzyme within the salvage path of NAD synthesis. In rodents, optimization of OT-82 dosing and nutritional niacin further expanded the compound’s therapeutic index. In toxicological studies conducted in rodents and nonhuman primates, OT-82 demonstrated no cardiac, nerve or retinal toxicities observed along with other NAMPT inhibitors coupled with no impact on mouse aging or durability. Hematopoietic and lymphoid organs were recognized as the main targets for dose restricting toxicity of OT-82 both in species. These results reveal strong dependence of neoplastic cells of hematopoietic origin on NAMPT and introduce OT-82 like a promising candidate to treat hematological malignancies.