CB002

CB002 is a small-molecule xanthine analog that restores p53 pathway signaling in cancer cells harboring TP53 mutations. Identified through a functional screen of the Chembridge library, CB002 induces the expression of the pro-apoptotic protein NOXA (PMAIP1) and activates p73-mediated transcription. It also promotes the ubiquitin-mediated degradation of mutant p53 protein. Unlike other xanthines such as caffeine, CB002 targets an S-phase cell cycle checkpoint, leading to increased phosphorylation of RPA2 and ATR, and the downregulation of proteins essential for DNA synthesis and repair. Preclinical studies have demonstrated its efficacy in colorectal cancer models and patient-derived organoids, showing selective cytotoxicity toward tumor cells without significant effects on normal human fibroblasts.