CDK8 kinase and its paralog CDK19 are the only kinase components of the mediator complex recognized as a key regulatory complex of RNA polymerase II-dependent transcription. Several reports indicated that CDK8 kinase could be pharmacologically targeted as a therapeutic approach in oncology (Pelish et al. Nature, 2015, Porter et al. PNAS, 2012).
SEL120 is a project focused on the development of a small-molecule, selective CDK8 kinase inhibitors, with potential application in the treatment of hematological malignancies, and solid tumors characterized by deregulated transcription. Clinical candidate compound SEL120-34A has shown strong single-agent efficacy in multiple animal models of acute myeloid leukemia, mantle cell lymphoma, colorectal cancer, breast cancer and Wilms’ tumors.
The mechanism of action is highly differentiated from CDK 1,2,4,6,7 and 9 inhibitors.
Gene expression profiling of tumors treated by SELl120-34A revealed modulation of cancer stemness as well as survival and chemo-/radiotherapy resistance mechanisms.
SEL120-34A –related increase in number of NK and NK-like T cells observed in vivo may be further explored as an alternative approach in the immune-oncology.
SEL120-34A completed a series of non-GLP toxicology studies in cynomolgus monkeys and advanced into IND-enabling studies. Initiation of clinical development of the program is planned for 2018.