Abstract: The invention provides compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein the variables are as described herein. The compounds or their pharmaceutically acceptable salts can inhibit the G12D mutant of Kirsten rat sarcoma (K-Ras) protein and are expected to have utility as therapeutic agents, for example, for treating cancer. The invention also provides pharmaceutical compositions which comprise compounds of Formula (I) or pharmaceutically acceptable salts thereof. The invention also relates to methods for use of the compounds or their pharmaceutically acceptable salts in the therapy and prophylaxis of cancer and for preparing pharmaceuticals for this purpose.

Abstract: Peptidomimetic macrocycles that comprise all-D configuration ?-amino acids and bind mouse double minute 2 (MDM2 aka E3 ubiquitin-protein ligase) and MDMX (aka MDM4) are described. These all-D configuration ?-amino acid 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 peptidomimetic macrocycles may be useful in anticancer therapies, particularly in combination with chemotherapy or radiation therapy.

Abstract: The present invention relates to non-membrane disruptive and p53 activating stapled peptides, as well as methods of treatment of cancer involving the use of these peptides. In one embodiment, the peptide comprises or consist of the amino acid sequence of TSFXaa1EY-WXaa3LLXaa2, where Xaa1 is (R)-2-(7?-octenyl)alanine or derivative thereof, or is (R)-2-(4?-pentenyl)alanine or derivative thereof; and Xaa2 and Xaa3 are independently any type of amino acid or modified amino acid. In another embodiment, the peptide comprising or consisting of the amino acid sequence of TSFXaa1EYW Xaa3LLXaa2ENXaa5, wherein Xaa1 and Xaa3 are any type of amino acid or modified amino acid; Xaa2 is S, or P, or (S)-2-(4?-pentenyl)alanine or a derivative of (S)-2-(4?-pentenyl)alanine; and wherein Xaa5 is F or Y.

Abstract: The present invention relates to non-membrane disruptive and p53 activating stapled peptides, as well as methods of treatment of cancer involving the use of these peptides. In one embodiment, the peptide comprises or consist of the amino acid sequence of TSFXaa1EYWXaa3LLXaa2, where Xaa1 is (R)-2-(7?-octenyl)alanine or derivative thereof, or is (R)-2-(4?-pentenyl)alanine or derivative thereof; and Xaa2 and Xaa3 are independently any type of amino acid or modified amino acid. In another embodiment, the peptide comprising or consisting of the amino acid sequence of TSFXaa1EYW Xaa3LLXaa2ENXaa5, wherein Xaa1 and Xaa3 are any type of amino acid or modified amino acid; Xaa2 is S, or P, or (S)-2-(4?-pentenyl)alanine or a derivative of (S)-2-(4?-pentenyl)alanine; and wherein Xaa5 is F or Y.