Preclinical Development Of Nsc-801845, A New Cytidine Analog, In Comparative Cell Culture And Xenograft Studies With The Clinical Candidates T-Dcyd And Aza-T-Dcyd

Cytidine analogs remain an area of active drug discovery and development with four FDA approved drugs. DNMT1, a maintenance methyltransferase that contributes to the hypermethylation and silencing of tumor suppressor genes, is a major molecular target of these agents. In addition, DNMT1 has roles independent of its methyltransferase activity and DNMT1 knockout results in decreased cell viability preceded by events consistent with activation of DNA damage response. 49-thio-29-deoxycytidine (T-dCyd) and 5-aza-49-thio-29-deoxycytidine (aza-T-dCyd) are two cytidine analogs that deplete DNMT1 both in vitro and in vivo in tumor cells. T-dCyd and aza-T-dCyd are currently in Phase I clinical trial at The National Cancer Institute (T-dCyd (NCT02423057) and aza-T-dCyd (NCT03366116)). Herein NSC-801845, a new cytidine analog, is compared with T-dCyd and aza-T-dCyd in cell culture and mouse xenograft studies in HCT-116 human colon carcinoma, BL0382 human bladder carcinoma, OVCAR3 human ovarian carcinoma, NCI-H23 human NSCLC carcinoma, and HL-60 human leukemia. In a 7-day monolayer culture cytotoxicity experiment, NSC-801845 was more potent than T-dCyd and less potent than aza-T-dCyd. In the 5 cell lines listed, the IC50s for NSC-801845 ranged from 3.7 uM to 0.2 uM in the 7-day experiment. In xenograft studies, T-dCyd was the least effective of the three cytidine analogs. In three of five xenograft lines (HCT-116, HL-60 and BL-0382), NSC-801845 was more efficacious than aza-T-dCyd (administered at the MTD of 1.5 mg/kg, IP). Comparable activity was observed for these two agents against the NCI-H23 and OVCAR3 xenografts. In the HCT-116 study, NSC-801845 (dosed 10 mg/kg IP, QDx5 for 4 cycles), produced complete regression of the tumors in all mice with a response that proved durable out to 150 days. Similarly, complete tumor regression was observed in the HL-60 leukemia xenograft when mice were dosed with NSC-801845 (10 mg/kg IP, QDx5 for 3 cycles). In the BL-0382 bladder study, oral and IP dosing of NSC-801845 (8 mg/kg PO, QDx5 for 3 cycles; 8 mg/kg IP QDx5, QDx5 for 3 cycles) produced regressions that showed tumor regrowth 13-days post dosing. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261200800001E. NCI-Frederick is accredited by AAALACi and follows the Public Health Service Policy on the Care and Use of Laboratory Animals. These studies were conducted on an approved Institutional Animal Care and Use Committee approved protocol. Citation Format: Joel Morris, Donn Wishka, Omar Lopez, Beverly A. Teicher, Raymond Divelbiss, Suzanne Borgel, Kyle Georgius, John Carter, Howard Stotler, Jerry Collins, Melinda Hollingshead. Preclinical development of NSC-801845, a new cytidine analog, in comparative cell culture and xenograft studies with the clinical candidates T-dCyd and aza-T-dCyd [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1961.