Discovery and development of small molecule inhibitors of Hdm2-p53 and Hdmx-p53 interactions

Shreya Datta, Purdue University

Abstract

Upregulation of structurally homologous oncoproteins, Hdm2 and Hdmx, has been linked to the onset of a large proportion of human cancers through depletion and inactivation of their common regulation target, the p53 tumor suppressor protein. Restoration of p53 function, rendered dormant by these negative regulators, establishes, therefore, a unique opportunity for targeted induction of apoptosis in wild-type p53 cancers. While several small molecules have been reported to antagonize the Hdm2–p53 interaction, these agents displayed minimal effectiveness against Hdmx, and few Hdmx-specific inhibitors have been disclosed. Here, we describe the use of a bacterial genetic selection system and an encoded large library of conformationally preorganized peptides (≥ 108 members) by E. coli cells to perform functional profiling of recognition motifs specific for each regulator to reveal key features guiding the antagonism of Hdm2–p53 and Hdmx–p53 interactions. The selected sequences that displayed optimal activity and target discrimination were processed further through site-directed mutagenesis and focused library synthesis to yield key insights into elements needed for effective antagonism of these structurally related oncoproteins. Structure-activity relationship analysis of the most effective leads and their derivatives identified the functional motifs necessary to discriminate effectively between the two closely related receptors, while providing convenient starting points for further optimization. The goal of the research is to understand the roles of the negative regulators in the modulation of various p53-mediated responses and develop chemotherapeutic strategies based on delicately controlled reactivation of p53 in cancer.

Degree

Ph.D.

Advisors

Savinov, Purdue University.

Subject Area

Molecular chemistry|Biochemistry

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