Targeting Hdm2 and Hdm4 in Anticancer Drug Discovery: Implications for Checkpoint Inhibitor Immunotherapy

• Published in: Cells (Basel, Switzerland) Vol. 13; no. 13; p. 1124
• Main Author: Ntwasa, Monde
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 29.06.2024
• Subjects: Animals; anticancer drugs; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic drugs; Antitumor activity; Apoptosis; cancer; Cell cycle; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - metabolism; Chromosomes; Drug delivery; Drug development; Drug Discovery; Drugs; Genes; Genotype & phenotype; Hdm2; Hdm4; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunosuppressive agents; Immunotherapy; Immunotherapy - methods; Interfaces; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - therapy; oncology; p53 Protein; Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Proto-Oncogene Proteins c-mdm2 - metabolism; Search engines; Tumor suppressor genes; Tumor Suppressor Protein p53 - metabolism; Tumors; Hdm4; cancer; Hdm2; immune checkpoint inhibitors; anticancer drugs; oncology
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells13131124

Hdm2 and Hdm4 are structural homologs that regulate the tumor suppressor protein, p53. Since some tumors express wild-type p53, Hdm2 and Hdm4 are plausible targets for anticancer drugs, especially in tumors that express wild-type p53. Hdm4 can enhance and antagonize the activity of Tp53, thereby playing a critical role in the regulation of p53's activity and stability. Moreover, Hdm2 and Hdm4 are overexpressed in many cancers, some expressing wild-type Tp53. Due to experimental evidence suggesting that the activation of wild-type Tp53 can augment the antitumor activity by some checkpoint inhibitors, drugs targeting Hdm2 and Hdm4 may be strong candidates for combining with checkpoint inhibitor immunotherapy. However, other evidence suggests that the overexpression of Hdm2 and Hdm4 may indicate poor response to immune checkpoint inhibitors. These findings require careful examination and scrutiny. In this article, a comprehensive analysis of the Hdm2/Hdm4 partnership will be conducted. Furthermore, this article will address the current progress of drug development regarding molecules that target the Hdm2/Hdm4/Tp53 partnership.