MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future - Pharmacological Review

Sep 21, 2026

MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future reviews the oncogenic functions of MDM2 and the rationale for targeting MDM2 in molecular targeted cancer therapy. The text outlines how MDM2 contributes to resistance mechanisms across chemotherapy/radiotherapy, tyrosine kinase inhibitor therapy, and immune checkpoint blockade. It surveys major strategies including MDM2–p53 interaction blockade, direct MDM2 small molecules, proteolysis-targeting chimeras, and dual inhibitors, then summarizes preclinical evidence, pharmacology/toxicology, combination approaches, and clinical trial progress, concluding with challenges and future directions.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages40

Reading Time1 h 41 min

AccessFree to download

Abstract

Signiﬁcance Statement

Introduction

The Rationale for Targeting MDM2 for Molecular Targeted Therapy

The Oncogenic Roles of MDM2

The Functions of MDM2 in the Resistance to Cancer Therapy

Major Strategies for Targeting MDM2

Blocking the MDM2-p53 Interaction

Small Molecules Directly Targeting MDM2

Proteolysis-Targeting Chimeras

Dual Inhibitors

Preclinical Studies of MDM2 Inhibitors

Eﬃcacy

Pharmacology and Toxicology

Combination Therapies to Overcome Drug Resistance

Clinical Trials of MDM2 Inhibitors

Pharmacology and Safety Evaluations

Clinical Eﬃcacy

Challenges and Future Directions

Blocking versus Direct Targeting

Dual Inhibitors of MDM2 and MDMX

1521-0081/76/3/414–453$35.00 PHARMACOLOGICAL REVIEWS Copyright © 2024 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4 .0 International license. [dx.doi.org/10.1124/pharmrev.123.001026](dx.doi.org/10.1124/pharmrev.123.001026)[ ](dx.doi.org/10.1124/pharmrev.123.001026)[Pharmacol Rev 76:414](Pharmacol Rev 76:414)–[453](453), [May 2024](May 2024) ASSOCIATE EDITOR: MICHAEL GOTTESMAN MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future Wei Wang,1 Najah Albadari,1,2 Yi Du, JosefF. Fowler, Hannah T. Sang, Wa Xian, Frank McKeon, Wei Li, Jia Zhou, and Ruiwen Zhang Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.) Abstract .................................................................................. 415 Signiﬁcance Statement .................................................................... 415 I. Introduction .............................................................................. 415 II. The Rationale for Targeting MDM2 for Molecular Targeted Therapy ......................... 425 A. The Oncogenic Roles of MDM2 ........................................................ 425 B. The Functions of MDM2 in the Resistance to Cancer Therapy ................................ 427 1. Chemo-and Radioresistance ....................................................... 427 2. Tyrosine Kinase Inhibitor Resistance .............................................. 428 3. Immune Checkpoint Inhibitor Resistance ................................................ 428 III. Major Strategies for Targeting MDM2 ..................................................... 428 A. Blocking the MDM2-p53 Interaction ................................................... 429 1. Peptide-Based MDM2 Inhibitors ................................................... 429 2. Small-Molecule Inhibitors Blocking the MDM2-p53 Interaction ..................... 429 a. Single-ring core derivatives ...................................................... 429 b. Bicyclic and multicyclic core derivatives ............................................. 431 c. Other core structures .......................................................... 431 B. Small Molecules Directly Targeting MDM2 ............................................. 432 C. Proteolysis-Targeting Chimeras ....................................................... 432 D. Dual Inhibitors ....................................................................... 434 IV. Preclinical Studies of MDM2 Inhibitors .................................................... 435 A. Efﬁcacy .............................................................................. 435 B. Pharmacology and Toxicology of Agents Targeting MDM2 ............................... 436 C. MDM2 Inhibition-Based Combination Therapies to Overcome Drug Resistance .......... 437 1. Combined Use with Chemotherapy and Radiotherapy .............................. 437 2. The Use of an MDM2 Inhibitor in Combination with Targeted Therapy .............. 438 3. The Combination of MDM2 Inhibition with Immunotherapy ........................ 439 Address correspondence to: Dr. Wei Wang, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 4349 Martin Luther King Blvd, Houston, Texas [77204. E-mail: wwang4@central.uh.edu](77204. E-mail: wwang4@central.uh.edu); or Dr. Ruiwen Zhang, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 4349 Mart

FAQs

Why is MDM2 targeted in molecular targeted cancer therapy?

MDM2 is targeted because it has oncogenic roles and contributes to multiple resistance pathways, including resistance to chemotherapy and radiotherapy, tyrosine kinase inhibitors, and immune checkpoint inhibitors.

What are the main strategies for inhibiting MDM2?

The review covers blockade of the MDM2-p53 interaction (including peptide and small-molecule approaches), direct small-molecule targeting of MDM2, proteolysis-targeting chimeras, and dual inhibitors.

How are MDM2 inhibitors evaluated beyond mechanism of action?

The document organizes evidence into preclinical studies, including efficacy and pharmacology/toxicology, followed by combination therapy approaches and sections on clinical trials with pharmacology/safety and clinical efficacy.

Sep 21, 2026

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