PROTAC CDK9 degrader-4 is a PROTAC protein degrader that targets CDK9 (cyclin-dependent kinase 9). PROTAC CDK9 degrader-4 contains two functional moieties: one end specifically recognizes and binds to CDK9, while the other end recruits an E3 ubiquitin ligase, thereby inducing ubiquitination and subsequent proteasomal degradation of CDK9. CDK9 is overexpressed in multiple cancers. Inhibition of CDK9 can suppress c-Myc and Mcl-1 and reactivate epigenetic silenced genes, which is a promising therapeutic target for transcription-driven malignant tumors[1].
In vitro, PROTAC CDK9 degrader-4 inhibited the growth of MDA-MB-468, MDA-MB-231, and BT-549 cells with IC₅₀ values of 15.0, 13.6, and 3.9nM, respectively[1].
In vivo, intratumoral administration of PROTAC CDK9 degrader-4 (0.15mM, 10µL) reduced CDK9 protein levels by 54% in MDA-MB-231 mice xenograft tumors at 16h post-injection relative to vehicle controls, while CDK7 protein levels remained unchanged[1]. PROTAC CDK9 degrader-4 (2.5 and 5mg/kg/d; i.p.; 7 days) inhibited tumor growth with slight body weight loss, reduced the average tumor volume by ~50%, and markedly decreased the levels of CDK9, MYC, and Ki-67 in MDA-MB-231 mouse xenografts[1].
References:
[1] Wei D, Wang H, Zeng Q, et al. Discovery of Potent and Selective CDK9 Degraders for Targeting Transcription Regulation in Triple-Negative Breast Cancer. J Med Chem. 2021;64(19):14822-14847.