Abstract
We demonstrate functionalized spiroligomers that mimic the HDM2-bound conformation of the p53 activation domain. Spiroligomers are stereochemically defined, functionalized, spirocyclic monomers coupled through pairs of amide bonds to create spiro-ladder oligomers [1]. Two series of spiroligomers were synthesized, one of structural analogs and one of stereochemical analogs, from which we identified compound 1, that binds HDM2 with a Kd value of 400 nM. The spiroligomer 1 penetrates human liver cancer cells through passive diffusion and in a dose-dependent and time-dependent manner increases the levels of HDM2 more than 30-fold in Huh7 cells in which the p53/HDM2 negative feed-back loop is inoperative. This is a biological effect that is not seen with the HDM2 ligand nutlin-3a. We propose that compound 1 modulates the levels of HDM2 by stabilizing it to proteolysis, allowing it to accumulate in the absence of a p53/HDM2 feedback loop.
Highlights
The need for new chemical agents that bind proteins and modulate protein function in vivo provides a fundamental challenge for chemists
Molecules that are intermediate in size between small molecule drugs (,600 Daltons) and antibodies (,150,000 Daltons) could provide new chemical entities capable of binding to the large, flat protein surfaces in a way that could disrupt protein-protein interactions and modulate protein function [2]. aHelices are the most commonly observed secondary structure in proteins and frequently act as interfacing domains in proteinprotein interactions [3,4]
We describe the synthesis and biological properties of a series of spiroligomers, which bind HDM2 in the cleft of the p53 transactivation domain
Summary
The need for new chemical agents that bind proteins and modulate protein function in vivo provides a fundamental challenge for chemists. We further show that one spiroligomer, compound 1, penetrates human liver cancer cells via passive diffusion and increases the levels of HDM2 in vivo. CANDO is able to vary back-bone stereochemistry and conformations as well as side-chain conformations to identify spiroligomers that could present functional groups to mimic the presentation of the Ca-Cb bond vectors of residues Phe19, Trp23 and Leu26 of p53 bound to HDM2 from the X-ray crystal structure [3].
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