MK256 is a novel CDK8 inhibitor with potent antitumor activity in AML through downregulation of the STAT pathway
Metrics: PDF 644 views | Full Text 2054 views | ?
Jen-Chieh Lee1,2,*, Shu Liu1,*, Yucheng Wang1,*, You Liang1 and David M. Jablons1
1 Thoracic Oncology, Department of Medicine, University of California, San Francisco, CA 94143, USA
2 Touro University, College of Osteopathic Medicine, Vallejo, CA 94592, USA
* These authors contributed equally to this work
|Jen-Chieh Lee,||email:||[email protected]|
|Shu Liu,||email:||[email protected]|
Keywords: AML; CDK8; kinase inhibitor; STAT pathway; xenograft
Received: July 28, 2022 Accepted: October 12, 2022 Published: November 02, 2022
Acute myeloid leukemia (AML) is the most lethal form of AML due to disease relapse. Cyclin dependent kinase 8 (CDK8) is a serine/threonine kinase that belongs to the family of Cyclin-dependent kinases and is an emerging target for the treatment of AML. MK256, a potent, selective, and orally available CDK8 inhibitor was developed to target AML. We sought to examine the anticancer effect of MK256 on AML. In CD34+/CD38- leukemia stem cells, we found that MK256 induced differentiation and maturation. Treatment of MK256 inhibited proliferation of AML cell lines. Further studies of the inhibitory effect suggested that MK256 not only downregulated phosphorylated STAT1(S727) and STAT5(S726), but also lowered mRNA expressions of MCL-1 and CCL2 in AML cell lines. Efficacy of MK256 was shown in MOLM-14 xenograft models, and the inhibitory effect on phosphorylated STAT1(S727) and STAT5(S726) with treatment of MK256 was observed in vivo. Pharmacologic dynamics study of MK256 in MOLM-14 xenograft models showed dose-dependent inhibition of the STAT pathway. Both in vitro and in vivo studies suggested that MK256 could effectively downregulate the STAT pathway. In vitro ADME, pharmacological kinetics, and toxicity of MK256 were profiled to evaluate the drug properties of MK256. Our results show that MK256 is a novel CDK8 inhibitor with a desirable efficacy and safety profile and has great potential to be a promising drug candidate for AML through regulating the STAT pathway.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.