MD-265 is a PROTAC degrader targeting MDM2, which activates p53 in cancer cells carrying wild-type p53. MD-265 induces MDM2 degradation by recruiting the CRL4-CRBN ligase complex via the ubiquitination and proteasomal degradation pathway. MD-265 upregulates p53 target genes, induces apoptosis, reduces Mcl-1 levels, increases caspase-3 cleavage, and inhibits colony formation of wild-type p53 leukemia stem cells. MD-265 can be used in research related to leukemia and acute myeloid leukemia [1] [2]. (Pink: MDM-2/p53 ligand; Blue: Cereblon ligand; Black: linker).
In Vivo, MD-265 (25 mg/kg; i.v.; every other day; 14 days) achieves complete, persistent tumor regression in RS4;11 xenograft mice without toxicity, and remains effective against regrown tumors with 3 doses of 25 mg/kg i.v[1]. MD-265 (25-50 mg/kg; i.v.; weekly) increases median survival of mice with disseminated RS4;11 leukemia by at least 24.5 days, or ≥31%[1]. MD-265 (25 mg/kg; i.v.; once a week; 7 weeks) provides a significant survival benefit in AML PDX models, with complete tumor burden reduction, delayed leukemia repopulation post-treatment, and an acceptable tolerability profile[2].
In Vitro, MD-265 (1 nM-1 μM; 4 days) potently inhibits the proliferation of RS4;11 leukemia cells carrying wild-type p53, with an IC50 of 0.7 nM, and shows no activity in p53-mutant RS4;11Mut cells[1]. MD-265 (1 nM-10 μM; 4 days) potently inhibits the proliferation of MV4;11 leukemia cells carrying wild-type p53, with an IC50 of 2 nM[1]. MD-265 (serial dilution; 4 days) potently inhibits the growth of multiple wild-type p53 acute leukemia cell lines, with an IC50 value ranging from 0.9 nM to 212 nM[1]. MD-265 (1-10 nM; 2 h) depletes MDM2 protein and activates p53 in RS4;11 wild-type p53 leukemia cells, and this effect is exerted at concentrations as low as 1 nM after 2 h of treatment[1]. MD-265 (3-30 nM; 2 h) activates p53, and treatment at concentrations as low as 3 nM for 2 h does not upregulate MDM2 protein in MV4;11 wild-type p53 leukemia cells[1]. MD-265 (10 nM; 3 h) treatment of RS4;11 wild-type p53 leukemia cells significantly elevates the mRNA expression of p53 target genes MDM2, p21 and PUMA by 8–10 fold after 3 h incubation, while showing no impact on TP53 mRNA levels[1]. MD-265 (30 nM; 3 h) upregulates the mRNA levels of p53 target genes MDM2, p21 and PUMA in MV4;11 wild-type p53 leukemia cells after 3 hours of treatment, but has no effect on TP53 mRNA[1]. MD-265 (3 nM; 2 h) induces MDM2 degradation and p53 activation in RS4;11 wild-type p53 leukemia cells, and this effect can be abrogated by co-treatment with 20 μM Lenalidomide [1]. MD-265 (serial dilutions; 4 days) exhibits cell growth inhibitory activity in wild-type p53 RS4;11 leukemia cells following 4 days of incubation, and this activity can be attenuated by combination treatment with 20 μM Lenalidomide[1]. MD-265 (serial dilutions; 4 days) exerts growth inhibitory effects on wild-type p53 MV4;11 leukemia, and combination with 20 μM Lenalidomide attenuates this activity[1]. MD-265 (serial dilution; 4 days) requires effective simultaneous binding to both MDM2 and cereblon to exert potent cell growth inhibitory effects on RS4;11 wild-type p53 leukemia cells[1]. MD-265 (10-100 nM; 2 weeks) inhibits colony formation in sensitive primary human AML LSCs, but exerts no effect on drug-resistant primary human AML LSCs[2]. MD-265 (72 h) potently induces cytotoxicity in primary human AML LSCs, with a median IC50 of 16 nM, and sensitivity is restricted to LSCs with functional TP53 and detectable MDM2/MDM4 expression[2]. Studies on MD-265 (72 h) show that normal human CD34+ hematopoietic stem and progenitor cells (HSPCs) are 100-fold less sensitive to it than primary human acute myeloid leukemia stem cells (AML LSCs), with a median IC50 of 818 nM[2]. MD-265 (10-1000 nM; 4 h) depletes MDM2 protein, induces p53, and activates apoptotic pathways in sensitive primary human AML LSCs, without triggering feedback upregulation of MDM2[2].
References:
[1]. Aguilar A, et al. Discovery of MD-265: A Potent MDM2 Degrader That Achieves Complete Tumor Regression and Improves Long-Term Survival of Mice with Leukemia. Journal of medicinal chemistry. 2024 Nov 14;67(21):19503-19518.
[2]. Kandarpa M, et al. Activity of PROTAC MDM2 degrader in primary leukemia cells and PDX models. Leukemia. 2026 May;40(5):918-924.
In Vivo, MD-265 (25 mg/kg; i.v.; every other day; 14 days) achieves complete, persistent tumor regression in RS4;11 xenograft mice without toxicity, and remains effective against regrown tumors with 3 doses of 25 mg/kg i.v[1]. MD-265 (25-50 mg/kg; i.v.; weekly) increases median survival of mice with disseminated RS4;11 leukemia by at least 24.5 days, or ≥31%[1]. MD-265 (25 mg/kg; i.v.; once a week; 7 weeks) provides a significant survival benefit in AML PDX models, with complete tumor burden reduction, delayed leukemia repopulation post-treatment, and an acceptable tolerability profile[2].
In Vitro, MD-265 (1 nM-1 μM; 4 days) potently inhibits the proliferation of RS4;11 leukemia cells carrying wild-type p53, with an IC50 of 0.7 nM, and shows no activity in p53-mutant RS4;11Mut cells[1]. MD-265 (1 nM-10 μM; 4 days) potently inhibits the proliferation of MV4;11 leukemia cells carrying wild-type p53, with an IC50 of 2 nM[1]. MD-265 (serial dilution; 4 days) potently inhibits the growth of multiple wild-type p53 acute leukemia cell lines, with an IC50 value ranging from 0.9 nM to 212 nM[1]. MD-265 (1-10 nM; 2 h) depletes MDM2 protein and activates p53 in RS4;11 wild-type p53 leukemia cells, and this effect is exerted at concentrations as low as 1 nM after 2 h of treatment[1]. MD-265 (3-30 nM; 2 h) activates p53, and treatment at concentrations as low as 3 nM for 2 h does not upregulate MDM2 protein in MV4;11 wild-type p53 leukemia cells[1]. MD-265 (10 nM; 3 h) treatment of RS4;11 wild-type p53 leukemia cells significantly elevates the mRNA expression of p53 target genes MDM2, p21 and PUMA by 8–10 fold after 3 h incubation, while showing no impact on TP53 mRNA levels[1]. MD-265 (30 nM; 3 h) upregulates the mRNA levels of p53 target genes MDM2, p21 and PUMA in MV4;11 wild-type p53 leukemia cells after 3 hours of treatment, but has no effect on TP53 mRNA[1]. MD-265 (3 nM; 2 h) induces MDM2 degradation and p53 activation in RS4;11 wild-type p53 leukemia cells, and this effect can be abrogated by co-treatment with 20 μM Lenalidomide [1]. MD-265 (serial dilutions; 4 days) exhibits cell growth inhibitory activity in wild-type p53 RS4;11 leukemia cells following 4 days of incubation, and this activity can be attenuated by combination treatment with 20 μM Lenalidomide[1]. MD-265 (serial dilutions; 4 days) exerts growth inhibitory effects on wild-type p53 MV4;11 leukemia, and combination with 20 μM Lenalidomide attenuates this activity[1]. MD-265 (serial dilution; 4 days) requires effective simultaneous binding to both MDM2 and cereblon to exert potent cell growth inhibitory effects on RS4;11 wild-type p53 leukemia cells[1]. MD-265 (10-100 nM; 2 weeks) inhibits colony formation in sensitive primary human AML LSCs, but exerts no effect on drug-resistant primary human AML LSCs[2]. MD-265 (72 h) potently induces cytotoxicity in primary human AML LSCs, with a median IC50 of 16 nM, and sensitivity is restricted to LSCs with functional TP53 and detectable MDM2/MDM4 expression[2]. Studies on MD-265 (72 h) show that normal human CD34+ hematopoietic stem and progenitor cells (HSPCs) are 100-fold less sensitive to it than primary human acute myeloid leukemia stem cells (AML LSCs), with a median IC50 of 818 nM[2]. MD-265 (10-1000 nM; 4 h) depletes MDM2 protein, induces p53, and activates apoptotic pathways in sensitive primary human AML LSCs, without triggering feedback upregulation of MDM2[2].
References:
[1]. Aguilar A, et al. Discovery of MD-265: A Potent MDM2 Degrader That Achieves Complete Tumor Regression and Improves Long-Term Survival of Mice with Leukemia. Journal of medicinal chemistry. 2024 Nov 14;67(21):19503-19518.
[2]. Kandarpa M, et al. Activity of PROTAC MDM2 degrader in primary leukemia cells and PDX models. Leukemia. 2026 May;40(5):918-924.