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.