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A transformation of 3'-deoxyadenosine (3'-dA)

NUC-7738 is a ProTide transformation of 3'-deoxyadenosine (3'-dA), also known as cordycepin. 3’-dA has demonstrated potent anti-cancer activity in non-clinical studies, but has not been successfully developed as a chemotherapy due to its rapid breakdown by adenosine deaminase (ADA).

Similar to our other ProTides, NUC-7738 is designed to generate the active anti-cancer metabolites of 3’-dA directly inside cancer cells, bypassing the key resistance mechanisms of breakdown, transportation and activation. Translational work has indicated that the mono-, di- and triphosphate metabolites of NUC-7738 exert various effects which may all contribute to its anti-cancer activity.

In non-clinical studies, we examined the in vitro cytotoxic activity of NUC-7738 across a range of different solid and haematological human cancer cell lines, as compared with 3'-dA. In 16 of the 20 cell lines, NUC-7738 was found to be up to 185-times more potent than 3’-dA.

Number 1 in circle
Enters cancer cells independently of transporters

Similar to gemcitabine and other nucleoside analogs, 3'-dA requires the nucleoside transporter, hENT1, to cross the cancer cell membrane. The phosphoramidate moiety alters the chemical characteristics of NUC-7738 in such a way that it is able to enter cancer cells independently of nucleoside transporters.

Number 2 in circle
Pre-activated, bypassing the need for AK

The rate-limiting activation step of 3’-dA requires the addition of a phosphate group, in this case by an enzyme called adenosine kinase, or AK. This phosphorylated form of 3’-dA, 3’-deoxyadenosine monophosphate (3’-dAMP), is subsequently converted into 3’-deoxyadenosine diphosphate (3’-dADP), which is then converted to 3’-deoxyadenosine triphosphate (3’-dATP). Each of these metabolites may have anti-cancer activity (see MOA). Once inside the cancer cell, NUC-7738 releases 3’-dAMP and as such does not require AK for the rate limiting first phosphorylation step. 3’-dAMP in turn is converted into 3’-dADP and 3’-dATP.

Number 3 in circle
Resistant to breakdown
by ADA

3’-dA is rapidly broken down by the enzyme ADA, preventing its activation and generation of its active anti-cancer form. NUC-7738 is not a substrate for ADA and is therefore resistant to degradation by this enzyme. This results in significantly higher levels of the active anti-cancer metabolites 3’-dAMP, 3’-dADP and 3’-dATP inside cancer cells treated with NUC-7738 compared to 3’-dA.

Clinical Studies

We are developing NUC-7738 for patients with either solid tumours or haematological malignancies based on the broad activity seen in non-clinical studies. NUC-7738 is currently being evaluated in a Phase I study.

NuTide:701 study logo

Phase I, dose-escalation study of NUC-7738 in patients with advanced solid tumours

This study, which is designed to determine the recommended Phase II dose of NUC-7738, is currently enrolling patients with advanced solid tumours and will be expanded to include patients with lymphomas.


Recommended Phase II dose, safety and tolerability


Pharmacokinetics, anti-cancer activity (BOR, ORR, DoR, DoSD & PFS)


Biomarker evaluation, pharmacodynamics


62 years, female

2 prior lines
  1. Nivolumab + ipilimumab:
    discontinued within 1 month
  2. CK7 inhibitor:
    progressed within 1 month

Target lesion: 1 (pelvic side wall)

Metastatic lung

65 years, male

2 prior lines
  1. Carboplatin + Pemetrexed:
    progressed at 6 months
  2. Docetaxel:
    progressed at 4 months

Target lesions: 2 (both lung)

ESMO poster 2020