A step closer toward therapies for p63-related disorders.

Small molecules with low molecular weight are of interest for drug development, as they are more likely to be absorbed. In cancer research, p53 is often mutated in many tumors, and many small molecules targeting mutant p53 have been tested. One of such low molecular weight compounds is APR246/PRIMA-1(MET) that was identified as a compound targeting and reactivating p53 mutants based on a cell-based screening for rescuing the apoptotic activity of p53. Recently, we have reported two different model systems, (1) corneal epithelial cells differentiated from induced pluripotent stem cells (iPSCs) derived from reprogramming of patient fibroblasts and (2) skin organotypic reconstitution of patient-derived keratinocytes. We have shown that APR246/PRIMA-1(MET) can rescue epithelial differentiation defects caused by mutations in p63 that is a family member of p53 and shares high sequence and structural similarity with the p53 protein.(1) (,) (2) The rationale of the two cellular models for drug screening and the potential of APR246/PRIMA-1(MET) to restore visual impairment of patients are discussed (Fig. 1).