ALRN-6924 + carboplatin + pemetrexed

ALRN-6924 + carboplatin + pemetrexed is a combination regimen under clinical investigation for the treatment of cancer, particularly in patients with wild-type TP53 tumors. ALRN-6924 (also known as sulanemadlin) is a first-in-class, cell-permeating stapled peptide that mimics the N-terminal domain of the p53 tumor suppressor protein. It binds with high affinity to both MDM2 and MDMX (MDM4), endogenous inhibitors of p53, thereby reactivating p53 signaling in cells with non-mutant TP53. This leads to cell cycle arrest and apoptosis in tumor cells. Carboplatin is a platinum-based chemotherapeutic agent that induces DNA crosslinking and apoptosis, while pemetrexed is an antifolate chemotherapy that inhibits multiple enzymes involved in nucleotide synthesis. The rationale for combining these agents includes potential synergistic antitumor effects and the ability of ALRN-6924 to protect normal tissues from chemotherapy-induced toxicity by transiently arresting their cell cycle without protecting TP53-mutant cancer cells.