2. Academic Validation
  3. MD-4251: A First-in-Class Oral MDM2 Degrader Inducing Complete Tumor Regression with Single-Dose Administration

MD-4251: A First-in-Class Oral MDM2 Degrader Inducing Complete Tumor Regression with Single-Dose Administration

  • J Med Chem. 2025 Jul 10;68(13):13249-13267. doi: 10.1021/acs.jmedchem.5c00809.
Ranjan Kumar Acharyya 1,  Liyue Huang 1,  Angelo Aguilar 1,  Biao Hu 1,  Longchuan Bai 1,  Hoda Metwally 1,  Donna McEachern 1,  Wei Jiang 1,  Yu Wang 1,  Qiuxia Li 2,  Bo Wen 2,  Duxin Sun 2 3,  Shaomeng Wang 1 4 5 3
Affiliations

Affiliations

  • 1 Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 2 Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 3 Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4 Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 5 Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 40511819 DOI: 10.1021/acs.jmedchem.5c00809
Abstract

MDM2 is a key negative regulator of the tumor suppressor p53 and an attractive target for Cancer therapy. We report the discovery of MD-4251, the first orally efficacious MDM2 Degrader developed using PROTAC technology. MD-4251 induces potent and rapid MDM2 degradation in RS4;11 cells (DC50 = 0.2 nM; Dmax = 96% at 2 h), leading to robust p53 activation. It selectively inhibits the growth of acute leukemia cell lines with wild-type p53, with minimal activity in p53 mutant lines. MD-4251 shows excellent oral bioavailability in mice, favorable metabolic stability, and no CYP or hERG liabilities. A single oral dose induces sustained MDM2 depletion and attains complete tumor regression in vivo. These results support MD-4251 as a promising therapeutic candidate for cancers through depletion of MDM2.

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