Abstract 1178: Unbiased efficacy-based screening of small molecules highly selective against hematological malignancies revealed inhibitor of NAD synthesis
Authors: Korotchkina Lioubov , Joshi Sangeeta , Vujcic Slavoljub , Toshkov Ilya , Chernov Mikhail , Kazyulkin Denis , Andrianova Katerina , Polinsky Alexander , Chernova Olga , Gudkov Andrei V. 
Published: July 2017

Abstract
Effective anticancer drugs can be directed against cell lineage-specific, rather than tumor-specific, targets (i.e., androgen receptor, CD20, etc.). We sought to conduct systematic search for novel agents that are selectively cytotoxic to hematopoietic (HP) malignancies presumably targeting HP lineage-specific survival factors. Cell-based screening and subsequent validation of small-molecules in a broad panel of HP and non-HP cancer cell lines followed by a hit-to lead optimization of the selected class of compounds has led to a molecule named OT-82 characterized by highly selective cytotoxicity against all HP-derived cancers tested (14 cell lines, representing human AML, ALL, CML and lymphoma cells) active within single nanomolar range of concentrations. OT-82 killed sensitive cells by induction of apoptosis and was up-to 20-fold more toxic to HP-derived than to solid tumor-derived cell lines and normal primary cells of HP and non-HP origin. OT-82-based affinity chromatography of cell lysates followed by mass spectrometry led to the identification of nicotinamide phosphorybosyltransferase (NAMPT) as the OT-82 target. NAMPT catalyzes the rate limiting step in a major pathway of synthesis of NAD, an energy metabolism mediator and essential cofactor of PARP and sirtuins. NAMPT treatment caused dramatic reductions in cellular NAD levels. Nicotinic acid (NA, vitamin B3), a substrate for the alternative NAD synthesis pathway, protected cells from the cytotoxic effects of OT-82. Oral administration of OT-82 was efficacious in subcutaneous and systemic xenograft models of human AML, ALL, erythroleukemia and multiple myeloma including complete response in several models. Therapeutic doses of OT-82 in mice were significantly lower than maximal tolerated dose (MTD); toxicities observed at doses above MTD were largely limited to HP and lymphoid organs. Toxicity profile of OT-82 determined in GLP in mice and non-human primates was favorably different from that reported for other reported clinical stage NAMPT inhibitors and did not involve any detectable retinal or cardiac toxicity. These results indicate high lineage specific and malignant transformation-specific dependence of HP neoplastic cells on NAMPT, presumably due to the strong addiction of this cell type on the NAD levels, and highlight OT-82 as a prospective clinical candidate for the treatment of hematological malignancies.
Citation Format: Lioubov Korotchkina, Sangeeta Joshi, Slavoljub Vujcic, Ilya Toshkov, Mikhail Chernov, Denis Kazyulkin, Katerina Andrianova, Alexander Polinsky, Olga Chernova, Andrei V. Gudkov. Unbiased efficacy-based screening of small molecules highly selective against hematological malignancies revealed inhibitor of NAD synthesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1178. doi:10.1158/1538-7445.AM2017-1178