Development of Novel p16INK4a Mimetics as Anticancer Therapy
Annual rept. 15 Sep 2013-14 Sep 2014
MINNESOTA VETERANS RESEARCH INST MINNEAPOLIS MN
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Mesothelioma therapy is a highly fatal disease that has poorly effective therapy with dose-limiting side-effects. Low expression of the CDK4CDK6 inhibitor p16INK4a has been demonstrated in up to 90 of mesothelioma tumors. The objective of this application as a next step in the pursuit of this long term goal is to identify stabilized peptides that will mimic the interaction between p16INK4a and CDK46. The central hypothesis of this proposal is that protein-protein interactions can be replicated or disrupted by stabilized peptides that have been identified via the identification of pharmacophores of small peptides that interact with CDK46. The specific aims are as follows. 1 Determine structure-function relationships of overlapping peptides derived from p16INK4a that inhibit the activity of CDK46 and identify stabilized peptides that inhibit CDK46. 2 In vitro functional studies will be used to evaluate bioactivities of stabilized peptides. 3 In vitro ADME studies studies to evaluate the cell permeability, delivery, and efficacy of stabilized peptides.
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- Medicine and Medical Research