p53 mutant reactivator APR-548

An analog of eprenetapopt and an orally bioavailable, small molecule prodrug and reactivator of p53 mutants, with potential antineoplastic activity. Upon oral administration of p53 mutant reactivator APR-548, as a prodrug APR-548 is converted to its active form, 2-methylene-quinuclidin-3-one (MQ), which binds to mutant p53 proteins at their DNA-binding domain and restores wild-type p53 protein structure and activity. This reconstitutes endogenous p53 activity, blocks tumor cell cycle progression and induces apoptosis in tumor cells expressing the TP53 mutations. p53, a tumor suppressor and transcription factor normally activated upon DNA damage, is frequently mutated and overexpressed in cancer cells; it plays a key role in both DNA repair and the induction of apoptosis.