Does inhibition of PIM kinase represent a novel mechanism to regulate the activity of ABCG2?. (360G-Wellcome-090072_Z_09_Z)

£168,220

ABC efflux pumps such as ABCG2 play an important role in treatment success in several diseases including cancer, where they can confer resistance to chemotherapy. ABCG2 is also expressed in healthy tissues and therefore influences pharmacokinetic profiles of drugs in the body. Consequently, a great deal of effort has been directed towards generating drugs capable of inhibiting efflux pumps. Unfortunately, this strategy has been unsuccessful due to factors such as (i) poor understanding of the dr ug-pump interaction and (ii) poor selectivity of inhibitors to specific ABC proteins. Therefore, strategies involving modulation of expression, or cellular regulation, of pump activity have been explored. Recently the serine/threonine kinase Pim-1 has been demonstrated to modulate ABCG2 mediated resistance; thereby suggesting that the kinase acts as a regulatory protein. Our aim is to describe how phosphorylation by Pim-1 modulates ABCG2 activity. Our strategy will utilise purified proteins and systems have already been developed to enable this molecular strategy. The investigations will also provide proof-of-principle for restoration of sensitivity to chemotherapy by the novel strategy of inhibiting a regulator of ABCG2 activity.

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Grant Details

Amount Awarded 168220
Applicant Surname Callaghan
Approval Committee Molecules, Genes and Cells Funding Committee
Award Date 2009-10-06T00:00:00+00:00
Financial Year 2009/10
Grant Programme: Title Project Grant
Internal ID 090072/Z/09/Z
Lead Applicant Dr Richard Callaghan
Other Applicant(s) Prof Robert Ford, Prof Stefan Knapp
Partnership Value 168220
Planned Dates: End Date 2013-01-31T00:00:00+00:00
Planned Dates: Start Date 2010-02-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region South East