4'-Thio-2'-Deoxycytidine (TdCyd)

P1, N=50, Recruiting, National Cancer Institute (NCI) | Trial primary completion date: Sep 2023 --> Sep 2024

The gene deletion markedly attenuated cytotoxicity and growth inhibition mediated by decitabine, azacitidine and 5-aza-4'-thio-2'-deoxycytidine (aza-T-dCyd) in colon and breast cancer cells. Thus, DNMT1 deletion confers resistance to DNMTi, and their anti-cancer activity is determined by DNA damage effects. Patients with DNMT1 gene deletions may not respond to DNMTi treatment.

Two DNMT1 depleting agents aza-dCyd (5-aza-2'-deoxycytidine, decitabine) and aza-Cyd (5-aza-cytidine, azacitidine) are currently used for the treatment of myelodysplastic syndromes and acute myeloid leukemia, and have also been investigated for non-oncology indications such as sickle cell disease. Although similar in structure to decitabine (aza-dCyd) its metabolism and mechanism of action is different than that of aza-dCyd, resulting in less off target activity and less toxicity. The larger therapeutic index of aza-T-dCyd (DNMT1 depletion vs toxicity) in mice suggests that it would be a better clinical candidate to selectively deplete DNMT1 from target cells and determine whether or not depletion of DNMT1 is an effective target for various diseases.

Cell and animal models with concurrent mutations in TET2 and DNMT3A were sensitive to T-dCyd treatment. The mutations were detectable in human solid tumors and frequently occur in some hematological malignancies.

4'-Thio-2'-deoxycytidine (T-dCyd) and 5-aza-4’-thio-2’-deoxycytidine (aza-T-dCyd) are two cytidine analogs that deplete DNMT1 both in vitro and in vivo in tumor cells...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 dosing of NSC-801845 (8 mg/kg PO, QDx5, for 3 cycles) produced a regressions that showed tumor regrowth 10-days post dosing.

Cancer cells and animal models examined with TET2 and DNMT3A-mutant genotype are sensitive to T-dCyd treatment.