School of Medical Sciences


Optimised prodrugs for gene therapy

Project Leaders


Translational Therapeutics Main Page

 

CB1954 (Tretazicar, 5-[aziridin-1-yl]-2,4-dinitrobenzamide) has been developed as a prototypic nitroreductase (NTR) prodrug for gene therapy applications. However, CB1954 has significant limitations for application in humans, including dose-limiting hepatotoxicity at doses below those required for efficacy in preclinical models. In addition, it has poor formulation characteristics and bystander cell kill effects which limit utility in most gene therapy contexts.

The prodrug PR-104, currently in clinical development under the auspices of Proacta Inc., is an excellent prodrug for NTR with good physiochemical characteristics and a robust bystander effect. We are currently evaluating its utility in combination with the NfsB 'armed' conditionally replicating virus ONYX-411. In collaboration with Dr Jeff Smaill next generation PR-104A analogues are also under development to maximise the antitumour efficacy of this novel vector/prodrug combination.

PR-104
Tumour_treatment

Related publications


Singleton, D.C., Li, D., Bai, S.C., Syddall, S.P., Smaill, J.B., Shen, Y., Denny, W.A., Wilson, W.R., Patterson, A.V. The nitroreductase prodrug SN28343 enhances the potency of the systemically administered armed oncolytic adenovirus ONYX-41111NTR .Cancer Gene Therapy 2007,; 14: 953-967. (PMID:17975564)

Liu, S.C., Ahn, G.O., Kioi, M., Dorie, M.J., Patterson, A.V., Brown, J.M. Optimised Clostridium-directed enzyme prodrug therapy improves the antitumour activity of the novel DNA crosslinking agent PR-104. Cancer Research 2008; 68: 7995-8003. (PMID:18829557)

Dachs, G.A., Hunt, M.A., Syddall, S.P., Singleton, D.C., Patterson, A.V. Bystander or no bystander for gene directed enzyme prodrug therapy. Molecules 2009: 14 (11): 4517-4545. (PMID:19924084)

Singleton, D.C., Syddall, S.P., Bai, S.Y., Li, D., Denny, W.A., Wilson, W.R., Patterson, A.V. Oncolytic adenovirus ONYX-411-NTR enhances the antitumour efficacy of the bioreductive alkylator prodrug PR-104. European Journal of Cancer 2008; [12], s300.

Atwell GJ, Yang S, Pruijn FB, Pullen SM, Hogg A, Patterson AV, Wilson WR, Denny WA. Synthesis and Structure-Activity Relationships for 2,4-Dinitrobenzamide-5 mustards as Prodrugs for the Escherichia coli nfsB Nitroreductase in Gene Therapy. J Med Chem 2007;50:1197-212. (PMID: 17326614)

SEEK magazine, Issue 2, 2007. Maurice Wilkins Centre for Molecular Biodiscovery (link)

Patterson, A.V., Ferry, D.M., Edmunds, S.J., Gu, Y., Singleton, R.S., Patel, K., Pullen, S.M., Syddall, S.P., Hicks, K.O. Atwell, G.J., Yang, S., Denny, W.A. and Wilson, W.R. Mechanism of action and preclinical antitumor activity of the novel hypoxia-activated DNA crosslinking agent PR-104. Clinical Cancer Research 2007; 13: 3922-3932. (PMID:17606726)

Wilson, W.R., Hicks, K.O., Pullen, S.M., Ferry, D.M., Helsby, N.A. and Patterson, A.V. Bystander effects of bioreductive drugs: potential for exploiting tumor hypoxia with dinitrobenzamide mustards. Rad. Res., 167: 625-636, 2007. (PMID: 17523848)