Discovery of a selective CDK7 PROTAC against acute leukemia with low platelet toxicity - PubMed
3 hours ago
- #PROTAC
- #leukemia
- #CDK7
- A selective CDK7 PROTAC degrader called CXJ2080 was developed to target acute leukemia.
- CXJ2080 uses the VHL E3 ligase for selective degradation of CDK7 with high potency (DC50 of 0.88 nM and >98% efficiency).
- This approach avoids dose-dependent thrombocytopenia common with CDK7 inhibitors, sparing platelets due to low VHL expression in them.
- Mechanistically, CDK7 degradation disrupts the CDK7-cyclin H-MAT1 complex, inhibiting MYC signaling and activating the p53-p21 axis.
- CXJ2080 shows strong antileukemic activity in preclinical models while preserving normal PBMC function, indicating reduced hematotoxicity.