title: Targeting the MDM2-p53 Protein-Protein Interaction for New Cancer Therapy: Progress and Challenges.
abstract: MDM2 is a primary cellular inhibitor of p53. It inhibits p53 function by multiple mechanisms, each of which, however, is mediated by their direct interaction. It has been proposed that small-molecule inhibitors designed to block the MDM2-p53 interaction may be effective in the treatment of human cancer retaining wild-type p53 by reactivating the p53 tumor suppressor function. Through nearly two decades of intense efforts, a number of structurally distinct, highly potent, nonpeptide, small-molecule inhibitors of the MDM2-p53 interaction (MDM2 inhibitors) have been successfully designed and developed, and at least seven such compounds have now been advanced into human clinical trials as new anticancer drugs. This review offers a perspective on the design and development of MDM2 small-molecule inhibitors and discusses early clinical data for some of the MDM2 small-molecule inhibitors and future challenges for the successful clinical development of MDM2 inhibitors for cancer treatment.
authors.affiliation: University of Michigan Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.affiliation: University of Michigan Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: University of Michigan Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Angelo
authors.initials: A
authors.lastname: Aguilar
authors.affiliation: University of Michigan Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Denzil
authors.initials: D
authors.lastname: Bernard
authors.affiliation: University of Michigan Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Chao-Yie
authors.initials: CY
authors.lastname: Yang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D048288:Imidazolines / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy*; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D048288:Imidazolines; D007211:Indoles; C579783:RG7112; D013141:Spiro Compounds; D016159:Tumor Suppressor Protein p53; C000593797:SAR405838; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2