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CDK8 and CDK19 Small Molecule Inhibitors and Degraders
Dana-Farber
Small molecule
Immunology, Oncology
Hit To Lead or Lead Optimization
Overview
CDK8 and its paralog CDK19 are part of the Mediator complex that controls RNA polymerase II, the enzyme responsible for transcribing mRNA. Deregulation of CDK8 has been linked to many cancers including cancers of the breast, colon, leukemias, melanoma, pancreas, and prostate. Targeting CDK8/19 has been recognized and exploited for its potential as a cancer therapy as is shown by ongoing clinical trials focused on metastatic or advanced solid tumors, and blood cancers including AML and high-risk MDS. Furthermore, CDK8/19 inhibition may also offer treatment potential for patients with autoimmune disease. Preclinical studies have shown that CDK8/19 inhibition leads to an increase in regulatory T (Treg) cells protecting the body from an autoimmune response.
Researchers at DFCI have developed a portfolio of CDK8/19 pyrazolopyridine and steroid-based small molecule inhibitors as well as ProTaC degraders derived thereof. The compositions show potent and selective effects on CDK8 and CDK19 activity by either inhibition or degradation, making them a trove of attractive new molecules for further development into promising new therapeutics to treat cancer or autoimmune diseases.
Benefits
• Low single digit nM IC50 assay readouts predictive of high potency
• High CDK8/19 selectivity with negligible off-target binding as determined by broad kinome screening, predictive of low toxicity drug properties
Nathanael Gray, Thomas Sundberg, Alykhan Shamji, Ramnik Xavier, Liv Johannessen, Bernard Khor, Jose Perez
• US 11247991 B2 (2022.02.15)
Patent Family: US, EP, JP, CN, CA, AU
• US 11285144 B2 (2022.03.29)
Patent Family: US
• "Development of highly potent and selective steroidal inhibitors and degraders of CDK8". Hatcher, J. M. et al. ACS Medicinal Chemistry Letters, 9(6), 540–545
• "Development of highly potent and selective pyrazolopyridine inhibitor of CDK8/19". Hatcher, J. M. et al. ACS Med Chem Lett. 2021 Oct 22;12(11):1689-1693
