dCDK9-202 is a potent CDK9-PROTAC degrader with a DC50 value of 3.5 nM. It exhibits broad-spectrum antitumor activity and significantly disrupts oncogenic transcriptomes. dCDK9-202 activates Caspase-3/7, increases levels of cleaved PARP, and directly induces tumor cell apoptosis (apoptosis). It effectively inhibits the growth of TC-71 tumors without any observed toxicity in mice. dCDK9-202 is applicable for researching EGFR-driven cancers, such as sarcomas.

CDK9:3.5 nM (DC50)

dCDK9-202, at a concentration of 10 nM for 0-24 hours, significantly reduces CDK9 protein levels in TC-71 cells within 2 hours, achieving complete and nearly sustained degradation within 8 hours. At concentrations ranging from 0.1 nM to 1 μM over 24 hours, dCDK9-202 exhibits nanomolar-level proliferation inhibitory activity in 12 cancer cell lines derived from various tissues such as lung, liver, bone, and brain. In TC-71 cells, the IC₅₀ is 8.5 nM. dCDK9-202, at concentrations of 10-50 nM for 24 hours, activates Caspase-3/7, increases PARP cleavage levels, and directly induces apoptosis in TC-71 cells. Administered at 0.25-25 nM for 6 hours, dCDK9-202 significantly reduces the phosphorylation of the Ser2 residue in the CTD domain of RNA polymerase II (p-Rpb1 Ser2) and downregulates various short half-life proteins regulated by CDK9, which are closely associated with the oncogenesis of TC-71 cells.

Intravenous administration of dCDK9-202 (10 mg/kg, every other day for a total of 7 doses) significantly reduces the tumor volume and weight in a mouse xenograft model established with the TC-71 cell line.