Aza-TdCyd Oral Product - Phase 1 clinical study (partner)

Aza-TdCyd (CAS: 169514-76-5)

Nucleoside Analog

cGMP API - Type II DMF

Methylation-mediated silencing of genes is an epigenetic mechanism implicated in carcinogenesis; agents that inhibit this mechanism are of clinical interest because of their potential to re-activate silenced tumor suppressor genes.

Two DNA hypomethylating nucleosides, 5-azacytidine (azacytidine) and 5-aza-2'-deoxycytidine (decitabine) have been approved by the FDA for the treatment of patients with myelodysplastic syndromes and certain leukemias. The nucleoside analog 5-aza-4 -thio-2 -deoxycytidine (Aza-TdC) is incorporated into DNA, where it engages the active site of DNA methyltransferase I (DNMT1), a maintenance methyltransferase that contributes to the hypermethylation and silencing of tumor suppressor genes. DNMT1 can become trapped in a covalent complex with DNA, thus depleting free enzyme and inhibiting the normal maintenance methylation of CpG sites, resulting in re-activation of tumor suppressor genes.

Data suggest a correlation between Aza-TdC activity in solid tumor xenograft models and decreased levels of DNMT1. Aza-TdC offers an improvement over traditional DNA methyltransferase inhibitors by virtue of a higher incorporation rate into DNA at lower levels of cytotoxicity; Aza-TdC has greater antitumor activity than another recently developed DNMT1 inhibitor, TdCyd, in some solid tumor xenograft models. Treatment with Aza-TdC is anticipated to result in the inhibition of tumor growth due to DNMT1 depletion at oral doses that are well tolerated in extended dosing schedules.

An oral formulation is currently in a Phase 1 clinical trial with an undisclosed partner.