mdm2 degrader  (Ascentage Pharma)

Journal: Leukemia

Article Title: Activity of PROTAC MDM2 degrader in primary leukemia cells and PDX models

doi: 10.1038/s41375-026-02957-8

Figure Lengend Snippet: A IC50 values for MDM2 degrader MD-265 (green circles) and MDM2 inhibitor MI-1061 (red triangles) in primary leukemic stem cells ( N = 100). The values above the line are samples with relative resistance to the inhibitor and degrader. Patient samples resistant to the degrader were also resistant to the inhibitor. B Dose-response curves for MD-265 and MI-1061 in primary LSCs; green curves denote relatively resistant samples. C Median IC50 for MD-265 (MDM2 degrader) and MI-1061 (MDM2 inhibitor) in patient leukemic blasts. The sample size is indicated on top of the bars. Among resistant blasts, the LSCs that had no measurable response were excluded as their predicted IC50 was infinite. D Dose-response curves and IC50 (nM) for MD-265 (circles) and MI-1061 (triangles) in normal HSPCs. E Colony-forming unit (CFU) assay in methylcellulose for one representative sensitive AML (AML-60). Treatments are indicated under the bars: MD265 at 10 nM and 100 nM, MI1061 at 100 nM and 1000 nM, Revlimid alone at 20 nM and UT (no drug control). F CFU for a resistant AML (AML-491). G Colony-forming units from CD34+ HSPCs from a normal donor (N1376). For ( E , F , G ) cells were plated in duplicate wells, treatments are indicated under the bar, and averages are shown with standard deviations. For ( G ), one of three different normal CD34-positive HSPCs tested is shown.

Article Snippet: The authors declare the following competing financial interest(s): The University of Michigan has filed patent applications on this MDM2 degrader, which have been licensed to Ascentage Pharma Group.

Techniques: Colony-forming Unit Assay, Control

Journal: Leukemia

Article Title: Activity of PROTAC MDM2 degrader in primary leukemia cells and PDX models

doi: 10.1038/s41375-026-02957-8

Figure Lengend Snippet: A Molecular characteristics and their frequencies in samples sensitive to the MDM2 degrader. The number in the label depicts the number of samples that carried the gene variant. None and not determined (ND) do not exclude additional mutations. Other mutations include GATA2, SETD2, EPHA2, PMS2, GEN1, JAK2, RUNX1, PRPF40b, SRSF2, ERB4, B Molecular characteristics and their frequency in resistant samples. Other mutations include GATA2, SRSF2, NSD1, JAK2, DPYD, NTRK1.

Article Snippet: The authors declare the following competing financial interest(s): The University of Michigan has filed patent applications on this MDM2 degrader, which have been licensed to Ascentage Pharma Group.

Techniques: Variant Assay

Journal: Leukemia

Article Title: Activity of PROTAC MDM2 degrader in primary leukemia cells and PDX models

doi: 10.1038/s41375-026-02957-8

Figure Lengend Snippet: A Immunoblots of sensitive LSCs (AML-807) treated for 4 h with MD-265 or MI-1061 for MDM2 and p53; MCL-1, as a marker of apoptosis, is also shown; β-actin was used as a loading control. B Dose-response curves for MD-265 (circles) and MI-1061 (triangles) in LSCs (AML-807). C Immunoblots of sensitive primary LSCs (AML-397) treated for 4 h with MD-265 or MI-1061. MDM2, p53 and cleaved caspase-3 are shown as an indicator of apoptosis. D Dose-response curves for MD-265 (circles) and MI-1061 (triangles) in LSCs (AML-397). E Immunoblots to resistant primary AML (AML-703), MDM2 protein, p53 levels and Caspase-3 cleavage in inhibitor and degrader-treated cells (4 h) are shown. F Dose-response in resistant LSCs (AML-703) to MD-265 (circles) and MI-1061 (triangles). In ( B , D , F ) The dose response was measured after treatment for 72 h. Calculated IC50 values are shown in inset table.

Article Snippet: The authors declare the following competing financial interest(s): The University of Michigan has filed patent applications on this MDM2 degrader, which have been licensed to Ascentage Pharma Group.

Techniques: Western Blot, Marker, Control

Journal: Leukemia

Article Title: Activity of PROTAC MDM2 degrader in primary leukemia cells and PDX models

doi: 10.1038/s41375-026-02957-8

Figure Lengend Snippet: LSCs (CD34 positive) derived from an AML patient (AML-587) were injected into NSG-S mice via the tail vein, and treatment was started after the establishment of human cells detectable in the blood. After disease development, 4 mice were assigned to each treatment group: Vehicle, MD-265 and APG-115. A Human CD45-positive cells were measured in peripheral blood by flow cytometry weekly. Dosing: MD-265 25 mg/kg IV once a week; MDM2i, APG115, 200 mg/kg PO three times weekly. B Kaplan–Meier survival of mice bearing AML PDX. Median survival for vehicle-treated mice was 19 days, for APG-115 treated 345 days and for MD265 was undefined. Based on the Log-rank (Mantel-Cox) test, the survival difference p value was 0.0475. The arrow in A and B indicates when treatment was discontinued. Early mortality in mice treated with MDM2 inhibitor MI-1061 was associated with perforation during gavage and rapid loss of weight. AML-587 was associated with NPM1 and FLT3-ITD mutation with normal cytogenetics. One of 3 PDXs is shown in the figures.

Article Snippet: The authors declare the following competing financial interest(s): The University of Michigan has filed patent applications on this MDM2 degrader, which have been licensed to Ascentage Pharma Group.

Techniques: Derivative Assay, Injection, Flow Cytometry, Mutagenesis

Journal: BMC Cancer

Article Title: Mdm2 targeting via PROteolysis TArgeting Chimeras (PROTAC) is efficient in p53 wildtype, p53-mutated, and abemaciclib-resistant estrogen receptor-positive cell lines and superior to mdm2 inhibition

doi: 10.1186/s12885-025-14361-z

Figure Lengend Snippet: Intracellular signaling in MCF-7nat, MCF-7res, and T-47D cells as a function of PROTAC treatment with increasing concentrations. Cells were treated for 16 and 30 h with 2.5, 5.0, 10, and 20 µM PROTAC before cells lysis and protein isolation. Completely untreated and DMSO-treated (PROTAC solvent) cells served as negative controls. Representative Western Blots of mdm2, p53, p73, p21, E2F1, Rb, pRbSer608, pRbSer780, pRbSer795, and pRbSer807/811 are shown

Article Snippet: “PROTAC mdm2-degrader-2” was purchased from MedChemExpress (NJ 08852, USA).

Techniques: Lysis, Isolation, Solvent, Western Blot

Journal: BMC Cancer

Article Title: Mdm2 targeting via PROteolysis TArgeting Chimeras (PROTAC) is efficient in p53 wildtype, p53-mutated, and abemaciclib-resistant estrogen receptor-positive cell lines and superior to mdm2 inhibition

doi: 10.1186/s12885-025-14361-z

Figure Lengend Snippet: Intracellular signaling in MCF-7nat, MCF-7res, and T-47D cells as a function of AMG-232 treatment over a period of 48 h. Samples taken after 30 min, 2, 8, 16, 30, and 48 h intervals are shown. mdm2, p53, p73, p21, E2F1, Rb, pRbSer608, Ser780, Ser795, and Ser807/811 were analyzed

Article Snippet: “PROTAC mdm2-degrader-2” was purchased from MedChemExpress (NJ 08852, USA).

Techniques:

Journal: Journal of medicinal chemistry

Article Title: Discovery of MD-224 as a First-in-Class, Highly Potent and Efficacious PROTAC MDM2 Degrader Capable of Achieving Complete and Durable Tumor Regression

doi: 10.1021/acs.jmedchem.8b00909

Figure Lengend Snippet: (A) Co-crystal structure of MDM2 in a complex with MI-77301 (Cyan), (PDB ID: 5TRF); (B) Modeled structure of MDM2 complexed with MI-1061 (Yellow); (C) Chemical structures of MDM2 inhibitors MI-77301 and MI-1061.

Article Snippet: The University of Michigan has filed a number of patent applications on these MDM2 degraders reported in this study, which have been licensed to Oncopia Therapeutics, LLC.

Techniques:

Journal: Journal of medicinal chemistry

Article Title: Discovery of MD-224 as a First-in-Class, Highly Potent and Efficacious PROTAC MDM2 Degrader Capable of Achieving Complete and Durable Tumor Regression

doi: 10.1021/acs.jmedchem.8b00909

Figure Lengend Snippet: MDM2 degraders designed with various linkers to pomalidomide.

Article Snippet: The University of Michigan has filed a number of patent applications on these MDM2 degraders reported in this study, which have been licensed to Oncopia Therapeutics, LLC.

Techniques: Inhibition

Journal: Journal of medicinal chemistry

Article Title: Discovery of MD-224 as a First-in-Class, Highly Potent and Efficacious PROTAC MDM2 Degrader Capable of Achieving Complete and Durable Tumor Regression

doi: 10.1021/acs.jmedchem.8b00909

Figure Lengend Snippet: Design of PROTAC MDM2 degraders using MDM2 inhibitors and cereblon ligands.

Article Snippet: The University of Michigan has filed a number of patent applications on these MDM2 degraders reported in this study, which have been licensed to Oncopia Therapeutics, LLC.

Techniques:

Journal: Journal of medicinal chemistry

Article Title: Discovery of MD-224 as a First-in-Class, Highly Potent and Efficacious PROTAC MDM2 Degrader Capable of Achieving Complete and Durable Tumor Regression

doi: 10.1021/acs.jmedchem.8b00909

Figure Lengend Snippet: Western blotting analysis of MDM2 and p53 proteins in RS4;11 cells treated with MDM2 inhibitors MI-1061 and MI-1242, and MDM2 degraders 1 and 2. RS4;11 cells were treated for 2 h with each compound at indicated concentrations, and proteins were probed by specific antibodies. GAPDH, a constitutively expressed housekeeping protein, was used as the loading control. MDM2 and p53 levels were quantified using an imager and were normalized over the GAPDH loading control.

Article Snippet: The University of Michigan has filed a number of patent applications on these MDM2 degraders reported in this study, which have been licensed to Oncopia Therapeutics, LLC.

Techniques: Western Blot, Control

Journal: Journal of medicinal chemistry

Article Title: Discovery of MD-224 as a First-in-Class, Highly Potent and Efficacious PROTAC MDM2 Degrader Capable of Achieving Complete and Durable Tumor Regression

doi: 10.1021/acs.jmedchem.8b00909

Figure Lengend Snippet: Western blotting analysis of the effect of potential MDM2 degraders with various linkers on induction of MDM2 and p53 proteins. RS4;11 cells were treated for 2 h with each individual compound at indicated concentrations and proteins were probed by specific antibodies. GAPDH was used as the loading control. MDM2 and p53 levels were quantified using an imager and were normalized over the GAPDH loading control.

Article Snippet: The University of Michigan has filed a number of patent applications on these MDM2 degraders reported in this study, which have been licensed to Oncopia Therapeutics, LLC.

Techniques: Western Blot, Control

Journal: Journal of medicinal chemistry

Article Title: Discovery of MD-224 as a First-in-Class, Highly Potent and Efficacious PROTAC MDM2 Degrader Capable of Achieving Complete and Durable Tumor Regression

doi: 10.1021/acs.jmedchem.8b00909

Figure Lengend Snippet: MDM2 degraders with modifications of the cereblon ligand portion in compound 1

Article Snippet: The University of Michigan has filed a number of patent applications on these MDM2 degraders reported in this study, which have been licensed to Oncopia Therapeutics, LLC.

Techniques: Inhibition

Journal: Journal of medicinal chemistry

Article Title: Discovery of MD-224 as a First-in-Class, Highly Potent and Efficacious PROTAC MDM2 Degrader Capable of Achieving Complete and Durable Tumor Regression

doi: 10.1021/acs.jmedchem.8b00909

Figure Lengend Snippet: MDM2 degraders linked from different positions of lenalidomide.

Article Snippet: The University of Michigan has filed a number of patent applications on these MDM2 degraders reported in this study, which have been licensed to Oncopia Therapeutics, LLC.

Techniques: Inhibition

Journal: Journal of medicinal chemistry

Article Title: Discovery of MD-224 as a First-in-Class, Highly Potent and Efficacious PROTAC MDM2 Degrader Capable of Achieving Complete and Durable Tumor Regression

doi: 10.1021/acs.jmedchem.8b00909

Figure Lengend Snippet: Western blotting analysis of the effect of MDM2 degraders linked from three different tethering sites of lenalidomide on MDM2 and p53 protein levels in RS4;11 cell line. The MDM2 inhibitor MI-1061 and the MDM2 degrader MD-224 were included as controls. RS4;11 cells were treated for 2 h with each individual compound at the indicated concentrations and proteins were probed by specific antibodies. GAPDH was used as the loading control. MDM2 and p53 levels were quantified using an imager and were normalized over the GAPDH loading control.

Article Snippet: The University of Michigan has filed a number of patent applications on these MDM2 degraders reported in this study, which have been licensed to Oncopia Therapeutics, LLC.

Techniques: Western Blot, Control

Journal: Journal of medicinal chemistry

Article Title: Discovery of MD-224 as a First-in-Class, Highly Potent and Efficacious PROTAC MDM2 Degrader Capable of Achieving Complete and Durable Tumor Regression

doi: 10.1021/acs.jmedchem.8b00909

Figure Lengend Snippet: Potential MDM2 degraders designed using an VHL-1 ligand.

Article Snippet: The University of Michigan has filed a number of patent applications on these MDM2 degraders reported in this study, which have been licensed to Oncopia Therapeutics, LLC.

Techniques: Inhibition

Journal: Journal of medicinal chemistry

Article Title: Discovery of MD-224 as a First-in-Class, Highly Potent and Efficacious PROTAC MDM2 Degrader Capable of Achieving Complete and Durable Tumor Regression

doi: 10.1021/acs.jmedchem.8b00909

Figure Lengend Snippet: Western blotting analysis of MDM2, p53, p21 and cleaved PAPR proteins in RS4;11 cells treated with the MDM2 inhibitor MI-1061 and a potential MDM2 degrader 20. RS4;11 cells were treated for 12 h with each individual compound at indicated concentrations and each protein was probed by a specific antibody. GAPDH was used as the loading control. MDM2, p53, p21 and cleaved PARP levels were quantified using an imager and were normalized over the GAPDH loading control.

Article Snippet: The University of Michigan has filed a number of patent applications on these MDM2 degraders reported in this study, which have been licensed to Oncopia Therapeutics, LLC.

Techniques: Western Blot, Control

Journal: Journal of medicinal chemistry

Article Title: Discovery of MD-224 as a First-in-Class, Highly Potent and Efficacious PROTAC MDM2 Degrader Capable of Achieving Complete and Durable Tumor Regression

doi: 10.1021/acs.jmedchem.8b00909

Figure Lengend Snippet: Western blotting analysis for MDM2 and p53 protein levels after treatment with the MDM2 inhibitor MI-1061 and the MDM2 degraders MD-222 and MD-224 in (A) RS4;11 and (B) MV-4–11 cell lines. RS4;11 or MV-4–11 cells were treated with each individual compound at the indicated concentrations for 2 h and proteins were probed by specific antibodies. GAPDH was used as the loading control. MDM2 and p53 protein levels were quantified using an imager and were normalized over the GAPDH loading control.

Article Snippet: The University of Michigan has filed a number of patent applications on these MDM2 degraders reported in this study, which have been licensed to Oncopia Therapeutics, LLC.

Techniques: Western Blot, Control

Journal: Journal of medicinal chemistry

Article Title: Discovery of MD-224 as a First-in-Class, Highly Potent and Efficacious PROTAC MDM2 Degrader Capable of Achieving Complete and Durable Tumor Regression

doi: 10.1021/acs.jmedchem.8b00909

Figure Lengend Snippet: Investigation of activity dependence of the MDM2 degraders MD-222 and MD-224 and the MDM2 inhibitor MI-1061 on cereblon (CRBN)-binding, proteasome and neddylation. (A). Western blotting analysis of MDM2 and p53 proteins in RS4;11 cells. RS4;11 cells were treated with the MDM2 inhibitor MI-1061, the MDM2 degrader MD-222 or MD-224 for 2 h in the presence or absence of excess lenalidomide. MDM2, p53 and GAPDH (loading control) proteins were probed with specific antibodies. (B, C). Cell growth inhibition activity of the MDM2 inhibitor MI-1061 and the MDM2 degraders MD-222 and MD-224 in the absence or presence of lenalidomide in the RS4;11 cell line. Cells were treated for 4 days with MI-1061, MD-222 or MD-224 alone or in combination with indicated concentrations of lenalidomide for 4 days and cell viability was determined by a WST-8 assay. (D). Western blotting analysis of MDM2 and p53 proteins in RS4;11 cells. RS4;11 cells were treated with DMSO, MG-132 (10μM), PR-171 (1μM) or MLN4924 (3μM) for 4 hours, followed by treatment with DMSO control, MDM2 inhibitor MI-1061, or the MDM2 degrader MD-224 for additional 2 h. MDM2, p53 and GAPDH (loading control) proteins were probed with specific antibodies.

Article Snippet: The University of Michigan has filed a number of patent applications on these MDM2 degraders reported in this study, which have been licensed to Oncopia Therapeutics, LLC.

Techniques: Activity Assay, Binding Assay, Western Blot, Control, Inhibition

Journal: Journal of medicinal chemistry

Article Title: Discovery of MD-224 as a First-in-Class, Highly Potent and Efficacious PROTAC MDM2 Degrader Capable of Achieving Complete and Durable Tumor Regression

doi: 10.1021/acs.jmedchem.8b00909

Figure Lengend Snippet: Control compounds 21 and 22 fail to induce MDM2 degradation and show much weaker activity in cell growth inhibition in the RS4;11 cell line: (A) Chemical structures of 21 and 22; (B) Western blotting analysis of p53 and MDM2 proteins in RS4;11 cells treated with MI-1061, MD-224, 21 and 22; (C) Cell growth inhibition of MI-1061, MD-224, 21 and 22 in the RS4;11 cell line.

Article Snippet: The University of Michigan has filed a number of patent applications on these MDM2 degraders reported in this study, which have been licensed to Oncopia Therapeutics, LLC.

Techniques: Control, Activity Assay, Inhibition, Western Blot

Journal: Journal of medicinal chemistry

Article Title: Discovery of MD-224 as a First-in-Class, Highly Potent and Efficacious PROTAC MDM2 Degrader Capable of Achieving Complete and Durable Tumor Regression

doi: 10.1021/acs.jmedchem.8b00909

Figure Lengend Snippet: qRT-PCR analysis mRNA levels of p53 target genes and TP53 after treatment with the MDM2 inhibitor, MI-1061 and the MDM2 degraders MD-222 and MD-224 in RS4;11 cells. RS4;11 cells were treated for 6 hr and mRNA levels of MDM2, p21, TP53, and PUMA were analyzed by qRT-PCR.

Article Snippet: The University of Michigan has filed a number of patent applications on these MDM2 degraders reported in this study, which have been licensed to Oncopia Therapeutics, LLC.

Techniques: Quantitative RT-PCR

Journal: Journal of medicinal chemistry

Article Title: Discovery of MD-224 as a First-in-Class, Highly Potent and Efficacious PROTAC MDM2 Degrader Capable of Achieving Complete and Durable Tumor Regression

doi: 10.1021/acs.jmedchem.8b00909

Figure Lengend Snippet: Flow cytometric analysis of apoptosis induction using Annexin V/ PI double staining after treatment with the MDM2 inhibitor, MI-1061, and the MDM2 degrader MD-224 in RS4;11 cells.

Article Snippet: The University of Michigan has filed a number of patent applications on these MDM2 degraders reported in this study, which have been licensed to Oncopia Therapeutics, LLC.

Techniques: Double Staining

Journal: Journal of medicinal chemistry

Article Title: Discovery of MD-224 as a First-in-Class, Highly Potent and Efficacious PROTAC MDM2 Degrader Capable of Achieving Complete and Durable Tumor Regression

doi: 10.1021/acs.jmedchem.8b00909

Figure Lengend Snippet: Pharmacodynamic (PD) analysis of MDM2, p53, p21 and PARP cleavage protein levels by western blotting after a single dose of MD-224 administered in the RS4;11 xenograft mouse model. A single dose of MD-224 (25 mg/kg, IV) effectively induces MDM2 degradation, p53 activation and PAPR cleavage in the xenograft RS4;11 tumors.

Article Snippet: The University of Michigan has filed a number of patent applications on these MDM2 degraders reported in this study, which have been licensed to Oncopia Therapeutics, LLC.

Techniques: Western Blot, Activation Assay