dCDK9-010 is a highly efficient and selective positive transcription elongation factor b (P-TEFb) complex PROTAC degrader with DC50 of 0.5 uM in NCI-H226 cells, recruits the MDM2 E3 ligase to induce proteasome-dependent degradation of CDK9 and all cyclin T isoforms.
dCDK9-010 displays no activity against a panel of CDK proteins and CDK9‐interacting proteins BRD4, Cyclin K, AFF1, or AFF4.
dCDK9-010 potently inhibits RNA polymerase II carboxy-terminal repeat domain phosphorylation and blocks MDM2-mediated p53 degradation, resulting in concurrent p53 pathway activation.
dCDK9-010 depleted significantly endogenous CDK9 and cyclin T at 500 nM in NCI-H460 non-small cell lung cancer cells, U87 glioblastoma cells, HCT116 colon cancer cells, and HT1080 fibrosarcoma cells.
dCDK9-010 is capable of inhibiting cell proliferation and inducing apoptosis.
dCDK9-010 (20 mg/kg, every other day, i.v.) significantly inhibited tumor growth in the NCI-H226 and TC-32 xenograft models in immunocompromised mice.