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Abstract

Disclosed are p53 peptidomimetic macrocycles, each p53 peptidomimetic macrocycle comprising an i, i+4 olefin staple and a polypeptide tail covalently linked to the p53 peptidomimetic macrocycle; an i, i+7 olefin staple and a polypeptide tail covalently linked to the p53 peptidomimetic macrocycle; or, an i, i+7 di-alkyne staple and optionally a polypeptide tail covalently linked to the p53 peptidomimetic macrocycle; wherein the p53 peptidomimetic macrocycle comprises all D-configuration amino acids and the polypeptide tail comprises three to nine amino acids, each amino acid of the polypeptide tail independently having a D-configuration or an L-configuration. The p53 peptidomimetic macrocycles are protease resistant, cell permeable without inducing membrane disruption, and intracellularly activate p53 by binding MDM2 and MDMX, thereby antagonizing MDM2 and MDMX binding to p53. These p53 peptidomimetic macrocycles may be useful in anticancer therapies, particularly in combination with chemotherapy or radiation therapy.

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First Claim