SynXT Therapeutics

The science of better health

A Paradigm Shift in Targeted Cancer Therapy

SynXT’s platform solves the fundamental “ROS deficit” that has plagued prodrug development for two decades.

The Three Components of Our Therapy

FAN-NM-CH₃: The Ultra-Sensitive Prodrug

This compound is a patented, inert prodrug that is specifically activated by high levels of reactive oxygen species (ROS)(1-3). Upon activation, it releases a potent DNA-alkylating nitrogen mustard payload, leading to targeted cancer cell death. Its boronic ester trigger responds to micromolar (μM) concentrations of hydrogen peroxide (H₂O₂), giving it a unique sensitivity to oxidative stress in the tumor microenvironment (3-5).

High-Dose Vitamin C: The Tumor-Selective Prooxidant

Repurposed to serve as a “booster,” this compound generates high, sustained fluxes of hydrogen peroxide (H₂O₂) specifically within tumors (6-9). It exploits a fundamental vulnerability of cancer cells—their reduced antioxidant capacity—which allows H₂O₂ to accumulate to therapeutic concentrations (≥100 µM) in the tumor microenvironment, while normal tissues, with higher antioxidant defenses, are able to clear it efficiently (10-13).

Optimized Dosing Protocol

A proprietary regimen defining the route, schedule, and dose of the combination to maximize therapeutic efficacy and selectivity.

The Mechanism of Action

The combination therapy of vitamin C (vitC) and the ROS-responsive prodrug FAN-NM-CH3 achieves potent and selective tumor killing through a multi-step mechanism that exploits the differential redox environment and genetic vulnerabilities between cancer and normal cells (10-13).

Basis for Selectivity

The high selectivity for cancer cells over normal cells is due to:

Differential Catalase Activity:

Normal cells have high inherent catalase activity and respond to vitC-induced oxidative stress by further upregulating catalase. This effectively neutralizes excess H₂O₂, preventing significant activation of the FAN-NM-CH3 prodrug and sparing normal tissue.

ROS Threshold: 

The basal ROS level in normal cells is too low to efficiently activate the prodrug without the vitC boost, which their robust antioxidant systems can mitigate.

Exploitation of p53 Dysfunction: 

Our therapy is designed to be effective across a broad TNBC population. We are concurrently developing TP53 mutation status as a predictive biomarker, as these tumors (over 75% of TNBC cases) exhibit impaired DNA repair and catalase dysregulation, making them particularly vulnerable to our approach. (31).

In summary, vitC acts as a “sensitizer” by creating a high-H₂O₂ environment, which FAN-NM-CH3 exploits as a “trigger” for its activation into a potent DNA-damaging agent. This strategy is uniquely effective against TP53-mutated cancers due to their inherent deficiency in DNA repair, resulting in a synergistic and highly selective anticancer effect.

References

  1. Peiro Cadahia, J., Previtali, V., Troelsen, N. S., & Clausen, M. H. (2019). Prodrug strategies for targeted therapy triggered by reactive oxygen species. Medchemcomm, 10(9), 1531-1549.
  2. Saxon, E., & Peng, X. (2022). Recent Advances in Hydrogen Peroxide Responsive Organoborons for Biological and Biomedical Applications. Chembiochem, 23(4), e202100366.
  3. Chen, W., et al. (2014). Reactive oxygen species (ROS) inducible DNA cross-linking agents and their effect on cancer cells and normal lymphocytes. J Med Chem, 57(11), 4498-4510.
  4. Kuang, Y., Balakrishnan, K., Gandhi, V., & Peng, X. (2011). Hydrogen peroxide inducible DNA cross-linking agents: targeted anticancer prodrugs. J Am Chem Soc, 133(48), 19278-19281.
  5. Chen, W., et al. (2018). Discovery and Optimization of Novel Hydrogen Peroxide Activated Aromatic Nitrogen Mustard Derivatives as Highly Potent Anticancer Agents. J Med Chem, 61(20), 9132-9145.
  6. Chen, Q., et al. (2005). Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci U S A, 102(38), 13604-13609.
  7. Chen, Q., et al. (2007). Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc Natl Acad Sci U S A, 104(21), 8749-8754.
  8. Chen, Q., et al. (2008). Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc Natl Acad Sci U S A, 105(32), 11105-11109.
  9. Yun, J., et al. (2015). Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science, 350(6266), 1391-1396.
  10. Liou, G. Y., & Storz, P. (2010). Reactive oxygen species in cancer. Free Radic Res, 44(5), 479-496.
  11. Gorrini, C., Harris, I. S., & Mak, T. W. (2013). Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov, 12(12), 931-947.
  12. Trachootham, D., Alexandre, J., & Huang, P. (2009). Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov, 8(7), 579-591.
  13. Nogueira, V., & Hay, N. (2013). Molecular pathways: reactive oxygen species homeostasis in cancer cells and implications for cancer therapy. Clin Cancer Res, 19(16), 4309-4314.
  14. Peng, X., & Gandhi, V. (2012). ROS-activated anticancer prodrugs: a new strategy for tumor-specific damage. Ther Deliv, 3(7), 823-833.
  15. Begleiter, A., Mowat, M., Israels, L. G., & Johnston, J. B. (1996). Chlorambucil in chronic lymphocytic leukemia: mechanism of action. Leuk Lymphoma, 23(3-4), 187-201.