Restoring guardianship of the genome: Anticancer drug strategies to reverse oncogenic mutant p53 misfolding

• Published in: Cancer treatment reviews 2018-12, Vol.71, p.19-31
• Main Authors: Babikir, Husam A., Afjei, Rayhaneh, Paulmurugan, Ramasamy, Massoud, Tarik F.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Cancer; Humans; Molecular Targeted Therapy - methods; Mutation; p53; Protein Folding; Protein misfolding; Small molecule drugs; Targeted therapy; Tumor Suppressor Protein p53 - chemistry; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0305-7372; 1532-1967
• DOI: 10.1016/j.ctrv.2018.09.004

•p53 (the guardian of the genome) is essential for maintenance of genetic stability.•P53 has been recognized as the most frequently mutated gene in human cancer.•A significant number of p53 mutations are structural and cause protein misfolding.•Therapeutic options to reactivate wild-type mutant misfolded p53 are underexplored.•We discuss lead drug compounds that can restore protein folding and function to p53. p53 is a transcription factor that activates numerous genes involved in essential maintenance of genetic stability. P53 is the most frequently mutated gene in human cancer. One third of these mutations are structural, resulting in mutant p53 with a disrupted protein conformation. Here we review current progress in a relatively underexplored aspect of p53-targeted drug development, that is, strategies to reactivate wild-type function of misfolded mutant p53. Unfortunately, most p53-targeted drugs are still at early stages of development and many of them are progressing slowly toward clinical implementation. Significant challenges need to be addressed before clinical translation of new anti-misfolding p53-targeted drugs.