Activity of PROTAC MDM2 degrader in primary leukemia cells and PDX models - PubMed
3 hours ago
- #PROTAC
- #MDM2 degrader
- #leukemia treatment
- MDM2 is a therapeutic target in wild-type TP53 tumors like acute myeloid leukemia (AML), where TP53 mutations are infrequent but p53 is often inactivated via MDM2 overexpression.
- MD-265 is a PROTAC degrader that recruits CRBN to degrade MDM2, restore p53 function, and induce apoptosis, showing higher potency (median IC50 of 16 nM in primary leukemic stem cells) compared to inhibitors like MI-1061.
- Resistance to MD-265 in leukemic stem cells with IC50 > 1 µM was linked to TP53 mutations, while normal hematopoietic stem cells showed much higher IC50 (818 nM), indicating selectivity.
- In PDX models using NSG-SGM3 mice, MD-265 treatment was non-toxic and prolonged survival, suggesting broad pre-clinical activity as a promising drug candidate for leukemia treatment.
- The research has competing financial interests, including patent applications licensed to Ascentage Pharma Group, with the authors involved in consulting and equity ownership.