NuCana develops phosphoramidate (ProTide) prodrugs that convert nucleoside analogs into monophosphate forms, enabling transporter‑independent cellular uptake and resistance to enzymatic degradation. This platform delivers higher intracellular concentrations of active metabolites, reducing toxic by‑products and improving safety in solid‑tumor chemotherapy, exemplified by NUC‑7738 and NUC‑3373, which are being evaluated as monotherapy and in combination with PD‑1 inhibitors.
Funding
Funding not disclosed
Founders
Product
Problem
Conventional nucleoside analog chemotherapies often suffer from poor cellular uptake, inefficient intracellular activation, rapid degradation by deaminases, and generation of toxic metabolites, which limit efficacy and increase adverse events for patients with solid tumors.
Solution
NuCana applies its proprietary phosphoramidate (ProTide) platform to convert nucleoside analogs into monophosphate prodrugs that bypass rate‑limiting activation steps and resist enzymatic breakdown. The ProTide design delivers higher intracellular concentrations of the active metabolite while minimizing off‑target toxic species, resulting in improved pharmacokinetics and safety profiles. Two clinical candidates illustrate this approach: NUC‑7738, which disrupts RNA polyadenylation and remodels the tumor microenvironment to enhance immunotherapy response, and NUC‑3373, a targeted thymidylate synthase inhibitor that generates potent FUDR‑MP levels with reduced infusion time and lower rates of neutropenia, mucositis, and hand‑foot syndrome. Early‑phase trials have shown encouraging anti‑cancer activity both as monotherapy and in combination with PD‑1 inhibitors across multiple solid‑tumor indications. By leveraging the ProTide chemistry, NuCana aims to deliver more effective, safer chemotherapy agents that can be integrated into existing treatment regimens and accelerate clinical development timelines.
Target Audience
Primary customers are oncologists and clinical researchers treating solid‑tumor cancers who require more potent and tolerable chemotherapy options, as well as pharmaceutical partners seeking to license or co‑develop ProTide‑based agents.
Features
- Phosphoramidate (aryl‑ester‑amino‑acid) motif that protects the nucleoside monophosphate from deamination and dehydrogenase degradation.
- Enhanced cellular uptake via passive diffusion and transporter‑independent delivery, leading to higher intracellular active‑metabolite concentrations.
- Optimized pharmacokinetic profile: shorter infusion durations (≈2 h vs. 46 h for 5‑FU) and extended plasma half‑life (~10 h for NUC‑3373).
- Reduced formation of toxic by‑products (e.g., FUTP, FBAL), translating into a more favorable safety and tolerability profile.
- Dual mechanism of action for NUC‑7738: inhibition of RNA polyadenylation plus modulation of the tumor microenvironment to potentiate checkpoint‑inhibitor efficacy.
- NUC‑3373’s potent thymidylate synthase inhibition generates DNA‑damage and immunogenic cell death, increasing MHC‑II expression and DAMP release.
- Clinical‑stage development with Phase 1/2 data in >300 patients across melanoma, colorectal, and other solid tumors, including combination studies with pembrolizumab.
- Broad patent portfolio covering composition‑of‑matter and method‑of‑use claims for ProTide derivatives.