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

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 (DC<sub>50</sub> = 0.2 nM; <i>D</i><sub>max</sub> = 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.

Authors

Institutions

Publication Details

Journal
Journal of Medicinal Chemistry
Published
2025-06-13
DOI
https://doi.org/10.1021/acs.jmedchem.5c00809
Citations
6
Primary Topic
Cancer-related Molecular Pathways
Type
article
Field-Weighted Citation Impact
6.27

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Angelo Aguilar, Ranjan Kumar Acharyya, Biao Hu, Wei Jiang et al.
6 citations
Journal of Medicinal Chemistry
Cancer-related Molecular Pathways
6.27
article

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

Angelo Aguilar, Ranjan Kumar Acharyya, Biao Hu, Wei Jiang, Hoda Metwally, Bo Wen, Qiuxia Li, Longchuan Bai, Donna McEachern, Duxin Sun, Shaomeng Wang, Yu Wang, Liyue Huang
article en
6 citations

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 (DC<sub>50</sub> = 0.2 nM; <i>D</i><sub>max</sub> = 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.

Journal of Medicinal ChemistryVol. 68(13)
University of Michigan (US), Medicina (PL), U-M Rogel Cancer Center (US)
NIH Clinical Center, Center for Scientific Review
Openalex Percentile: Top 3%
Cancer-related Molecular Pathways
6.27
DOISourceOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.