Development of Novel p16INK4a Mimetics as Anticancer Therapy.

摘要

Mesothelioma therapy is a highly fatal disease that has poorly effective therapy with dose-limiting side-effects. Low expression of the CDK4/CDK6 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 CDK4/6. 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 CDK4/6. The specific aims are as follows. (1) Determine structure-function relationships of overlapping peptides derived from p16INK4a that inhibit the activity of CDK4/6 and identify stabilized peptides that inhibit CDK4/6. (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.