Project Leader
Translational Therapeutics Main Page
All bioreductive prodrugs share a common mechanism of activation, undergoing
reductive metabolism by cellular enzymes called oxidoreductases to form
toxic species. The capacity for prodrugs to act as single-electron (1e)
acceptors is opposed by molecular oxygen and consequently they function as
direct oxygen sensors. However two-electron (2e) reduction can bypass this
oxygen inhibition step. It is important to understand which enzymes are relevant
and in what types of cancer they are found so that bioreductive prodrugs can be
used in an optimal clinical context.
PR104A (and analogues)
We seek to identify the human enzymes responsible for
the metabolic reduction (activation) of the prodrug PR-104A and its analogues.
To date we have shown that several diflavin oxidoreductases (POR, MTRR,
NDOR1, NOS2A) are involved in the hypoxic activation of
PR-104A. In addition, we have shown that aldo-keto reductase 1C3 can activate
PR-104A independent of a tissue oxygenation status. AKR1C3, is a
ketosteroid reductase that has not previously been described as an aerobic (2e)
nitroreductase. This oxygen-independent PR-104A activation raises the
possibility that it contributes to dose limiting myelotoxicity. In collaboration
with the ACSRC's Medicinal Chemistry group, we are currently
developing next generation analogues of PR-104A which are non-substrates for
reduction by AKR1C3.
 |
 |
|
Prodrug PR-104A bound in the active site of aldo-keto reductase 1C3 |
Lung cancer tissue microarray stained for aldo-keto reductase 1C3
(AKR1C3) expression |
Keywords: Prodrug,
Oxidoreductases,
Cytochrome P450
oxidoreductase, Aldo-keto
reductase 1C3
PR509 (and analogues)
The hypoxia-selective multikinase inhibitors
(HSMKIs) carry a permanent positive charge when in their deactivated (prodrug)
state. Cumulative experimental evidence indicates the positively charged HSMKI
prodrugs are cell excluded. Following reduction (activation) the positive charge
is lost and the MKI are free to diffuse into cancer cells and inhibit the target protein kinase
receptor activity. We are currently evaluating whether plasma membrane
(cell-surface) reductases are responsible for the reduction of these
novel agents. A library of candidate plasma membrane oxidoreductases have been
identified and cloned with the intention of elucidating their role in HSMKI
metabolism.
Keywords:
Hypoxia-selective multikinase inhibitors,
Target protein kinase receptor
Collaborators:
Medicinal
Chemistry Group,
Dr Gabi Dachs
Related publications
Guise,C.P., Abbattista,M.R., Tipparaju,S.R., Lambie,N.K., Su,J., Li,D.,
Wilson,W.R., Dachs,G.U., Patterson,A.V. Diflavin Oxidoreductases Activate the
Bioreductive Prodrug PR-104A under Hypoxia. Molecular Pharmacology 2012; 81 (1):
31-40. (PMID: 21984255)
Guise,C.P., Abbattista,M.R., Singleton,R.S., Holford,S.D., Connolly,J., Dachs,G.U.,
Fox,S.B., Pollock,R., Harvey,J., Guilford,P., Doñate,F., Wilson,W.R.,
Patterson,A.V. The bioreductive prodrug PR-104A is activated under aerobic
conditions by human aldo-keto reductase 1C3. Cancer Research 2010; 70 (4):
1573-1584. (PMID:20145130)
Jameson, M.B., Rischin, D., Pegram, M., Gutheil, J., Patterson, A.V., Denny,
W.A. and Wilson, W.R. A phase I pharmacokinetic trial of PR-104, a nitrogen
mustard prodrug activated by both hypoxia and aldo-ketoreductase 1C3, in
patients with solid tumors. Cancer Chemotherapy Pharmacology 2010; 65 (4):
791-801. (PMID:20012293).
Gu, Y., Guise, C.P., Abbattista, M., Lie, J., Sun, X., Atwell, G.J., Boyd, M.,
Patterson, A.V., Wilson, W.R. Reductive metabolism of the dinitrobenzamide
mustard anticancer prodrug PR-104 in mice. Chemotherapy Pharmacology 2011; 67
(3): 543-555. (PMID:20473609)
Gu, Y., Patterson, A.V., Atwell, G.J., Chernikova, S.B., Brown, J.M., Thompson,
L.H. and Wilson, W.R. Roles of DNA repair and reductase activity in the
cytotoxicity of the hypoxia-activated dinitrobenzamide mustard PR-104A.
Molecular Cancer Therapeutics 2009, 8 (6): 1714-1723. (PMID:19509245)
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)
Guise C.P., Wang A.T.W., Theil A., Bridewell D.J., Wilson W.R. and Patterson A.V.
Identification of human reductases that activate the dinitrobenzamide mustard prodrug
PR-104A: a role for cytochrome P450 reductase under hypoxia. Biochemical Pharmacology
2007; 74: 810-820. (PMID:17645874)
