Kimberly Stegmaier, MD
Principal Investigator, Pediatric Oncology, Dana-Farber
Co-Director, Pediatric Hematologic Malignancies Program, Dana-Farber/Boston Children’s Hospital
Ted Williams Chair, Professor of Pediatrics, Harvard Medical School
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Highly Potent and Selective CDK8/CDK19 Inhibitors Target Solid Tumors
Project Overview
- Two proteins, cyclin-dependent kinase 8 (CDK8) and its paralog CDK19, have emerged as important cancer targets, particularly in select solid cancers.
- Dana-Farber has developed a series of next-generation small molecule inhibitors and degraders of the CDK8/CDK19 kinases.
- The broad patent portfolio covering both CDK8/CDK19 inhibitors and degraders is available for licensing or for collaborative further development
Technology
CDK8 and CDK19 are cyclin-dependent kinases that are core components of the so-called Mediator complex that has essential roles as a positive and negative regulator of gene expression. The CDK8/19 proteins are over-expressed in certain cancers compared with normal cells, including colorectal cancer and some alveolar rhabdomyosarcoma (ARMS). In addition, data from the Dependency Map (Dep Map), which identifies essential genes across hundreds of cancer cell lines, highlights their role in multiple cancers underlining their potential as valuable targets for cancer drug development.
Emerging clinical validation from other researchers developing CDK8/19 inhibitors shows that some of their compounds display signs of clinical efficacy in early clinical Phase I/II testing for AML (Acute Myeloid Leukemia) and MDS (myelodysplastic syndrome) and relapsed or advanced solid tumors but with some toxicities. Recognizing the potential clinical value of targeting CDK8/19, Dana-Farber researchers seek to develop new CDK8/19 compounds without limiting toxicities.
Dana-Farber has a long, deep expertise in kinase inhibitor development. Part of that expertise includes work from John Hatcher, PhD, of Dana-Farber’s Medicinal Chemistry Core, who started developing small molecule kinase inhibitors more than ten years ago, with CDK8/CDK19 as a prime target. Over time, he has developed a portfolio of CDK8/19 small molecule inhibitors designed to overcome toxicities yet expected to perform well clinically. Several lead compounds show potent and selective effects on CDK8/CDK19 activity by either inhibition or degradation, making them attractive candidates for further development into promising new therapeutics to treat cancer.
When Kimberly Stegmaier, MD, of the Department of Pediatric Oncology at Dana-Farber observed that ARMS showed a top genetic dependency on CDK8/CDK19 according to her DepMap studies, she initiated tests comparing the lead Dana-Farber CDK8/19 inhibitors with other methods of CDK8/CDK19 inhibition. Using shRNA gene knockdown, CRISPR knockout, and Dana-Farber’s CDK8/19 kinase inhibitory small molecules, she observed that all demonstrated on-target activity. These results confirm a potential use of the compounds in ARMS.
Other research from Hatcher and Stegmaier shows that in neuroblastoma, the most common extracranial solid tumor in pediatrics, loss of CDK8/CDK19 sensitizes RAS-mutant neuroblastomas to destruction by MEK inhibitors. Preclinical studies show that CDK8/19 inhibitors also improve response to MEK inhibitors in RAS-pathway-activated neuroblastomas. Together, these findings raise the possibility of a new combination for RAS-mutant neuroblastomas using CDK8/CDK19/MEK inhibitors. The treatment strategy, yet to be tested in patients, may also have clinical relevance for other RAS-driven cancers.
In addition, research published in 2008 from the laboratory of William Hahn, MD, PhD, Professor of Medicine in the Department of Medical Oncology at Dana-Farber, revealed that CDK8/19 inhibition offers potential in malignancies like colorectal cancer that are driven by the beta-catenin signaling pathway. Their data reveals that suppression of CDK8/CDK19 inhibits tumors with high levels of CDK8/CDK19 and beta-catenin.
Team Members: Kimberly Stegmaier, MD, John Hatcher, PhD, Susu Zhang, PhD
Applications
Dana-Farber’s CDK8/CDK19 inhibitor development efforts are centered around three primary indications, namely ARMS, neuroblastoma, and colorectal cancer. Preclinical data suggests the compounds are well tolerated and display promising signs of efficacy.
Other potential applications include AML, MDS, and solid tumors such as breast, prostate, pancreas, lung, and melanoma.
Opportunities
Dana-Farber seeks collaborations and licensing partners to accelerate development and translation of the technology to patients.
Team Members
John Hatcher, PhD
Principal Scientist, Medicinal Chemistry Core, Dana-Farber
Susu Zhang, PhD
Postdoctoral Fellow, Stegmaier Lab, Dana-Farber
