Cyclin-dependent kinase 9 (CDK9), an important regulator of transcriptional elongation, is a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. We characterized NVP-2, a selective ATP-competitive CDK9 inhibitor, and THAL-SNS-032, a selective CDK9 degrader consisting of a CDK-binding SNS-032 ligand linked to a thalidomide derivative that binds the E3 ubiquitin ligase Cereblon (CRBN). To our surprise, THAL-SNS-032 induced rapid degradation of CDK9 without affecting the levels of other SNS-032 targets. Moreover, the transcriptional changes elicited by THAL-SNS-032 were more like those caused by NVP-2 than those induced by SNS-032. Notably, compound washout did not significantly reduce levels of THAL-SNS-032-induced apoptosis, suggesting that CDK9 degradation had prolonged cytotoxic effects compared with CDK9 inhibition. Thus, our findings suggest that thalidomide conjugation represents a promising strategy for converting multi-targeted inhibitors into selective degraders and reveal that kinase degradation can induce distinct pharmacological effects compared with inhibition.
The anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) contributes to the pathophysiology of acute myeloid leukemia (AML) and certain B-cell malignancies. Tumor dependence on Mcl-1 is associated with resistance to venetoclax. Voruciclib, an oral cyclin-dependent kinase (CDK) inhibitor targeting CDK9, indirectly decreases Mcl-1 protein expression and synergizes with venetoclax in preclinical models.
Drug abuse continues to pose a significant challenge in HIV control efforts. In our investigation, we discovered that cocaine not only upregulates the expression of the DNA-dependent protein kinase (DNA-PK) but also augments DNA-PK activation by enhancing its phosphorylation at S2056. Moreover, DNA-PK phosphorylation triggers the higher localization of the DNA-PK into the nucleus.
Cancer Minimally Invasive Therapies Centre, Guangdong Second Provincial General Hospital, Jinan University, Guangzhou 510632, Guangdong Province, China.
Colorectal cancer (CRC) ranks third in the number of cancers mainly because of the inability to diagnose it at an early stage. The pathogenesis of CRC is complicated, which is the result of the complex interaction of multiple genetic and environmental factors. Currently, one of the main treatments for CRC is chemotherapy.
Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
CDK9 plays a key role in cancer transcription and is a potential target for anti-cancer treatments, especially for blood cancers.
Inhibition of CDK9 reduces α-tubulin protein levels and promotes its degradation due to decreased acetylation, which is vital for microtubule stability.
The study reveals that CDK9 inhibitors downregulate the acetyltransferase ATAT1, compromising microtubule stability and highlighting a new therapeutic mechanism for CDK9 inhibitors in cancer treatment.
Cutaneous T-cell lymphoma (CTCL) is a type of skin cancer that affects T cells and can spread throughout the body, making current treatments like chemotherapy less effective and often accompanied by severe side effects.
Research has identified cyclin dependent kinase 9 (CDK9) as a key factor in CTCL growth, with specific malignant T-cell characteristics revealed through single-cell RNA sequencing.
Targeting CDK9 with specialized treatments like PROTACs not only significantly reduces CTCL cell growth but also, when combined with all-trans retinoic acid (ATRA), shows promise for more effective and complete treatment options.
