OT-82 is an Orally Active NAMPT Inhibitor with Antineoplastic Activity
Posted On 2020-06-04
Treatment of hematopoietic (HP) malignancies such as leukemia, lymphoma, and myeloma need improvement due to the drug high toxicity. Some effective anticancer agents are tissue-selective but not cancer-specific targets.
These agents cannot distinguish normal and transformed cells. Besides they are usually against lineage-specific metabolic deficiency or lineage-specific surface antigen, respectively.
NAMPT is the rate-limiting enzyme in the salvage pathway. It helps the synthesis of nicotinamide adenine dinucleotide (NAD) from nicotinamide.
Many NAMPT inhibitors show efficacy in cancer models. OT-82 is a potent, selective, and orally active inhibitor of NAMPT.
This compound is selectively toxic to cells of hematopoietic origin and induces cell death in an NAD+ dependent manner. OT-82 is a promising antineoplastic agent for the study of hematological malignancies.
Firstly, in vitro, OT-82 demonstrates tissue-selective (HP vs non-HP) cytotoxicity. It is against HP cell lines MV4–11, U937, RS4;11, and PER485 cell growth with IC50 values of 2.11 nM, 2.70 nM, 1.05 nM, and 1.36 nM, respectively. Additionally, It also against nonHP cell lines MCF-7, U87, HT29, and H1299 cell growth with IC50 values of 37.92 nM, 29.52 nM, 15.67 nM and 7.95 nM , respectively.
Next, this inhibitor also demonstrates cancer-selective (tumor vs normal) cytotoxicity. It is more sensitive to BMMNC from leukemia patients. The IC50 values are 31 nM and 7.10 nM for AML and ALL donors, respectively. In BMMNC from healthy donors, the IC50 value is 62.69 nM.
In MV4–11 cells, OT-82 inhibits recombinant NAMPT activity. At the same time, it causes dose-dependent reductions in cellular NAD and ATP concentrations. OT-82 results in the activation of caspase-3 and exhibits hallmarks of apoptotic cell death. Furthermore, it increases the proportion of cells with sub-G1 DNA content and depolarization of the mitochondrial membrane.
Lastly, OT-82 is orally active. In the SC xenograft model of Burkitt’s lymphoma in SCID mice. Treatment with OT-82 increases survival to 100% and 56% at 40 or 20 mg/kg, respectively.
In conclusion, OT-82, a novel NAMPT inhibitor and has efficacy against HP malignancies. It exhibits a favorable pharmacological profile and an excellent therapeutic index.
Korotchkina L, et al. Leukemia. 2020 Jan 2.