Abstract A063: TAS1553, a novel class of RNR inhibitor, demonstrates synergistic antitumor efficacy in combination with nucleoside analogues

Background: Ribonucleotide reductase (RNR) is an essential metabolic enzyme that catalyzes a rate-limiting step for de novo dNTP biosynthesis via converting ribonucleotides to deoxyribonucleotides. dNTPs are also supplied through nucleoside salvage pathway in which dNTP is synthesized from extracellular nucleoside. The salvage pathway is also utilized for conversion of several nucleoside analogues to their active metabolites. Given the previous report showing that the inhibition of de novo pathway activates salvage pathway at least in vitro, RNR is considered as a promising target for combination therapy with nucleoside analogues. However, in vivo efficacy of selective RNR inhibitor in combination with nucleoside analogues has not been clarified yet. Previously, we reported a novel class of RNR inhibitor TAS1553, which is a selective and orally available small molecule abrogating protein-protein interaction between RNR subunits. Here, we evaluated the synergistic activity of TAS1553 and several nucleoside analogues in vitro as well as in vivo studies. Material and methods: Antiproliferative activity was assessed by CellTiter-Glo® 2.0 assay. Intracellular and intratumoral ara-CTP amounts were measured by HPLC analysis. Antitumor efficacy was evaluated in athymic nude mice bearing MV-4-11 (human AML) and CFPAC-1 (human pancreatic cancer) cell line. Results: To examine whether TAS1553 plus nucleoside analogues combination shows synergistic efficacy, we evaluated antiproliferative activity of TAS1553 in combination with some nucleoside analogues (cytarabine, gemcitabine, decitabine, and 2F-ara-A) to calculate the combination index (CI). TAS1553 exhibited synergistic antiproliferative activity (CI Citation Format: Takuya Hoshino, Hiroyuki Ueno, Wakako Yano, Sayaka Tsukioka, Seiji Miyahara, Takamasa Suzuki, Kazutaka Miyadera, Teruhiro Utsugi, Takeshi Sagara. TAS1553, a novel class of RNR inhibitor, demonstrates synergistic antitumor efficacy in combination with nucleoside analogues [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A063. doi:10.1158/1535-7163.TARG-19-A063