p53 pathway targeting mechanics, architectures, and therapeutic advancements:

Abstract

Most, if not all, human cancers are caused by TP53 (p53) gene dysfunction. There are two main mechanisms causing this dysfunction: MDM2/MDM4-mediated wild-type p53 downregulation and mutation. p53 is a very desirable target for the creation of novel anticancer medications due to its nearly ubiquitous inactivation in cancer. While several approaches have been explored to target defective p53 in cancer treatment, only two of these tactics have produced drugs that are now undergoing clinical trial testing. These tactics include finding substances that can activate the p53 mutant back to its wild-type form and substances that can prevent the interaction of MDM2/MDM4 and wild-type p53.Many p53-MDM2/MDM4 antagonists are presently undergoing clinical trials; the most developed one is called idasanutlin, and it is being tested on patients with relapsed or refractory acute myeloid leukemia in a phase III clinical trial. APR-246 and COTI-2 are the two mutant p53-reactivating substances that have advanced to clinical testing. It is yet unknown if MDM2/MDM4 inhibitors and mutant p53-activating drugs have any clinical utility, despite encouraging results from their trials in preclinical models. Given the high frequency of p53 malfunction in human malignancies, a new era in cancer treatment is expected to dawn if any of the drugs presently undergoing clinical trial evaluation prove to be effective