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OT-82, a novel anticancer drug candidate that targets the strong dependence of hematological malignancies on NAD biosynthesis.

Authors
  • Korotchkina, Lioubov1
  • Kazyulkin, Denis1
  • Komarov, Pavel G1
  • Polinsky, Alex1
  • Andrianova, Ekaterina L1
  • Joshi, Sangeeta1
  • Gupta, Mahima1
  • Vujcic, Slavoljub1
  • Kononov, Eugene1
  • Toshkov, Ilia1
  • Tian, Yuan1
  • Krasnov, Peter1
  • Chernov, Mikhail V2
  • Veith, Jean2
  • Antoch, Marina P2
  • Middlemiss, Shiloh3
  • Somers, Klaartje3
  • Lock, Richard B3
  • Norris, Murray D3, 4
  • Henderson, Michelle J3
  • And 3 more
Type
Published Article
Journal
Leukemia
Publisher
Springer Nature
Publication Date
Jun 30, 2020
Volume
34
Issue
7
Pages
1828–1839
Identifiers
DOI: 10.1038/s41375-019-0692-5
PMID: 31896781
Source
Medline
Language
English
License
Unknown

Abstract

Effective treatment of some types of cancer can be achieved by modulating cell lineage-specific rather than tumor-specific targets. We conducted a systematic search for novel agents selectively toxic to cells of hematopoietic origin. Chemical library screenings followed by hit-to-lead optimization identified OT-82, a small molecule with strong efficacy against hematopoietic malignancies including acute myeloblastic and lymphoblastic adult and pediatric leukemias, erythroleukemia, multiple myeloma, and Burkitt's lymphoma in vitro and in mouse xenograft models. OT-82 was also more toxic towards patients-derived leukemic cells versus healthy bone marrow-derived hematopoietic precursors. OT-82 was shown to induce cell death by inhibiting nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the salvage pathway of NAD synthesis. In mice, optimization of OT-82 dosing and dietary niacin further expanded the compound's therapeutic index. In toxicological studies conducted in mice and nonhuman primates, OT-82 showed no cardiac, neurological or retinal toxicities observed with other NAMPT inhibitors and had no effect on mouse aging or longevity. Hematopoietic and lymphoid organs were identified as the primary targets for dose limiting toxicity of OT-82 in both species. These results reveal strong dependence of neoplastic cells of hematopoietic origin on NAMPT and introduce OT-82 as a promising candidate for the treatment of hematological malignancies.

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