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MD-4251

MD-4251 : Degrader (PROTAC) of MDM2

Structure

Information

  • MDM2
  • Degrader (PROTAC)
  • up to 30 nM

In Vitro Validations

No in Vitro Validations

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay, off target (cells): MD-4251 was evaluated for GSPT1, IKZF1/3, and CK1α, a number of known neo-substrates for cereblon ligands in Western blot after 2 h treatment, and had no effect on the levels of GSPT1 and IKZF3 and only had a modest effect on IKZF1 and CK1α.
Potency assay, off target (cells): Cellular degradation selectivity of MD-4251 was evaluated via an unbiased proteomics analysis. MD-4251 induced robust upregulation of p53 protein (TP53 gene product), MD-4251 also increased the levels of three other proteins, namely DSC1 (Desmocollin-1), NBEA (neurobeachin), and CASP14 (Caspase-14). Due to the low level of MDM2 protein, depletion of MDM2 protein was not detected in this proteomics experiment and no protein was reduced by more than 2-fold.
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SERP ratings and comments

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

The authors primarily used the RS4;11 cell line in most studies, and only cell growth inhibitory activities were evaluated in MV4-11 and MOLM-13. Therefore, attention would be required when utilizing other cell lines. The authors observed tumor growth inhibitory activity at a 3 mg/kg oral dose, but they only confirmed the degradation of MDM2 and upregulation of p53 at a 10 mg/kg and higher dose. Therefore, a 10 mg/kg or higher oral dose would be preferable for MOA studies.

(last updated: 8 Dec 2025 )

SERP Ratings

In Cell Rating
In Model Organisms

(last updated: 17 Dec 2025 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

At 30 nM, MD-4251 appears to have little effect on common off-targets (GSPT1, IKZF1/3, CK1a) at a 2 hr timepoint in RS4;11 cells. A caveat is that degradation proteomics was performed only at 3 nM @2 hrs, and so it is possible that higher concentrations and longer incubation times may lead to degradation of other targets. The probe appears comparable to KT-253, another CRBN-based PROTAC degrader of MDM2. An orthogonal probe The probe should be compared to another recent PROTAC degrader of MDM2: PMID: 39648478 is available.

(last updated: 26 Jan 2026 )