Related Experiment Video
Updated: Jun 21, 2026
High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
Published on: November 9, 2020
Discovery of selective CDK9 degraders with anti-AML activity using PROTAC technology
Qing Li1, Fuyuan Zhou2, Ding Luo3
1Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, PR China.
Abstract:
Cyclin-dependent kinase 9 (CDK9) has emerged as a pivotal therapeutic target in oncology, characterized by aberrant overexpression in both hematologic cancers and solid neoplasms. Selective CDK9 inhibition effectively disrupts transcriptional programs in tumor cells and induces apoptosis. Herein, we describe the generation of several proteolysis targeting chimeras (PROTACs) using the CDK9 inhibitor DRB as the core ligand. Compound D6 emerged as the most active degrader in this series, eliciting CDK9 degradation with a Dmax value of 45% in acute myeloid leukemia (AML) cells. The cellular activity of D6 was found to be 12 times higher than that of its parental inhibitor DRB, while showing no degradation activity toward other CDK family kinases. This enhanced antiproliferative activity was primarily mediated through increased induction of apoptosis. Furthermore, D6 suppressed tumor growth in vivo, achieving an inhibition rate of 31%, and demonstrated a favorable safety profile. Our findings indicate that D6 is a promising candidate worthy of further investigation, and that CDK9-targeted degradation is a valuable potential therapeutic option for AML.
Insights
Researchers developed a novel PROTAC molecule, D6, that effectively degrades Cyclin-dependent kinase 9 (CDK9) in acute myeloid leukemia (AML) cells. This targeted degradation approach shows promise as a new cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Cyclin-dependent kinase 9 (CDK9) is overexpressed in various cancers, making it a key therapeutic target.
- CDK9 inhibition disrupts tumor cell transcription and induces apoptosis.
Purpose of the Study:
- To design and evaluate novel proteolysis targeting chimeras (PROTACs) that induce targeted degradation of CDK9.
- To assess the efficacy and safety of a lead PROTAC compound, D6, in preclinical models of acute myeloid leukemia (AML).
Main Methods:
- Generation of PROTACs utilizing the CDK9 inhibitor DRB as a core ligand.
- Evaluation of CDK9 degradation and cellular activity in AML cell lines.
- Assessment of antiproliferative effects, apoptosis induction, and in vivo tumor growth inhibition.
Main Results:
- Compound D6 effectively degraded CDK9 in AML cells, with maximal degradation (Dmax) of 45%.
- D6 exhibited 12-fold higher cellular activity than its parent inhibitor DRB, with no off-target degradation of other CDK kinases.
- D6 demonstrated significant antiproliferative activity, enhanced apoptosis induction, and suppressed tumor growth in vivo by 31% with a good safety profile.
Conclusions:
- CDK9-targeted degradation via PROTACs is a viable therapeutic strategy for AML.
- Compound D6 is a potent and selective CDK9 degrader with significant preclinical efficacy and a favorable safety profile, warranting further clinical investigation.
More Related Videos
Related Concept Videos
02:15M-Cdk Drives Transition Into Mitosis
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
02:34Inhibition of Cdk Activity
02:57Targeted Cancer Therapies
There are several types of targeted therapies against specific...