CDK4 Subfamily (CDK4 & CDK6)
CDK4 and CDK6 are highly related cyclin-dependent kinases that control G1 phase of the cell cycle. While CDK4 is thought to be essential in all cells, CDK6 plays a role only in selective cell types and can be compensated for by CDK2. Dual CDK4/6 inhibitors have been approved for the treatment of hormone receptor-positive/HER2-negative breast cancer.
CDK4 Subfamily Inhibitors |
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|---|---|
| Cat. No. | Product Name / Activity |
| 4786 | PD 0332991 isethionate |
| Potent cdk4 and cdk6 inhibitor; brain penetrant | |
| 7050 | Ribociclib |
| Dual cdk4/cdk6 inhibitor; orally bioavailable | |
| 2609 | Ryuvidine |
| Cdk4 inhibitor; also SETD8 inhibitor | |
Degraders |
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| Cat. No. | Product Name / Activity |
| 6921 | BSJ-03-123 |
| Selective Cdk6 Degrader (PROTAC®) | |
| 6938 | BSJ-03-204 |
| Selective Cdk4/6 Degrader (PROTAC®) | |
| 6937 | BSJ-04-132 |
| Selective Cdk4 Degrader (PROTAC®) | |
CDK4 and CDK6
The CDK 4 subfamily of cyclin-dependent kinases consists of CDK4 and CDK6, which function interchangeably in most cell types during G1 phase of the cell cycle. Both CDK4 and CDK6 bind cyclin D, leading to phosphorylation and inactivation of retinoblastoma protein (Rb) and transcription of E2F target genes, which includes those responsible for cell cycle progression.
Cyclin D interacts with the N-terminal lobe of CDK4; however, no conformational change is induced by its binding and CDK4 is still inaccessible to substrates. The activation process for CDK4 is poorly understood, but it's thought that binding of cyclin D induces the activation segment to open and fit to the phospho-acceptor site.
Recent research has suggested that CDK6 is not essential for cell cycle progression in all cell types, and that in some cells CDK2 can perform the same role. CDK6-knockout mice have impaired hematopoetic cell function but otherwise develop normally. A role for CDK6 has been identified in the inhibition of T-cell differentiation, connecting it to immune system function. It has also been linked to the development of astrocyte morphology and stem cell types.
CDK6 and Viral-Induced Cancers
Kaposi's sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA virus that causes a pigmented skin sarcoma. In healthy individuals KSHV infection has no symptoms, however it can cause sarcoma in the immunocompromised, such as those receiving chemotherapy or with HIV infection. The genome of KSHV encodes a viral D-type cyclin that can bind CDK6, leading to overactivation of the cell cycle, which likely contributes to development of KSHV-related tumors.
CDK4/6 Inhibitors
Several CDK4/6 dual inhibitors have been approved for the treatment of cancer, specifically hormone receptor-positive/HER2-negative breast cancer; PD 0332991 (Cat. No. 4786) also known as Palcociclib, is a potent inhibitor of both CDK4 and CDK6, which induces G1-phase cell cycle arrest and cell senescence in Rb-proficient cell lines. Ribociclib (Cat. No. 7050) and Abermaciclib are also CDK4/CDK6 inhibitors approved for the treatment of breast cancers.
More recently, Protein Degraders that enable the investigation of CDK4 and CDK6 have been developed. Degraders harness a cell's ubiquitin-proteasome system to induce selective degradation of a cellular protein, through Targeted Protein Degradation. BSJ-03-204 (Cat. No. 6938) is a dual CDK4 and CDK6 Degrader, while BSJ-04-132 (Cat. No. 6937) is a selective CDK4 Degrader and BSJ-03-123 (Cat. No. 6921) is a selective CDK6 Degrader. All three of these compounds induce cereblon-dependent protein degradation in vitro and can be used to dissect the individual roles of CDK4 and CDK6 in the cell cycle.
Figure 1: Structure of CDK4 (orange) in complex with Cyclin D (green). Taken from Day et al (2009) Crystal Structure of Human Cdk4 in Complex with a D-Type Cyclin. Proc Natl Acad Sci U S A. 106, 4166. PMID: 19237565