CDK7 Inhibitors and Degraders for Treatment of Cancer and Inflammatory Diseases

Project Overview

• The high tumor mutation burden in small cell lung cancer (SCLC) provides a rationale for investigating the effect of immune checkpoint blockade (ICB) and developing new treatments that effectively trigger anti-tumor immunity and improve patient outcomes.
• Cyclin-dependent kinase 7 (CDK7) is crucial for cell cycle progression and gene transcription and represent an attractive target for ICB.
• Scientists at Dana-Farber have developed new, highly selective CDK7 inhibitors and degraders for ICB treatment of solid tumors.
• This technology is available for licensing for further development as a therapeutic to benefit patients.

Technology

Small cell lung cancer (SCLC), accounts for about 15% of lung cancers, is a deadly disease often affecting heavy smokers. Characterized by rapid growth and early metastasis, patients initially respond to chemotherapy but almost always recur within 6 to 12 months, resulting in a five-year survival rate below 7%. The high tumor mutation burden in SCLC provides a rationale for investigating the effect of immune checkpoint blockade. However, immune checkpoint inhibitors like atezolizumab (anti-PD-L1) have extended overall survival by only two months in clinical trials, and many patients do not respond to these therapies. This underscores the urgent need for new treatments that effectively trigger anti-tumor immunity and improve patient outcomes.

Cyclin-dependent kinase 7 (CDK7) is crucial for cell cycle progression and gene transcription and is the catalytic core of the CDK-activating kinase (CAK) complex. Previously identified inhibitors of CDK7, like THZ1 lacked specificity, also targeting CDK12/13 and complicating the study of CDK7’s distinct functions. Early clinical results point towards encouraging results with CDK7 inhibitors in solid tumors. However, these compounds have non-covalent, enzymatic mechanisms of action prone to lack of selectivity and development of resistance. This highlights the need for new drug combinations that can potentiate ICB SCLC by specifically inhibiting CDK7.

Dr. Nathanael Gray is one of the leading academic developers of inhibitors and degraders, particularly against kinases. His laboratory has developed novel, highly selective CDK7 inhibitors and degraders without off-target effects on the closely related CDK12/13, allowing precise investigation of CDK7’s role and starting points for further drug development. The covalent CDK7 inhibitors and degraders have an unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing a new way of achieving selectivity of CDK7.

Selective inhibition/degradation of CDK7 in SCLC cells disrupts cell cycle progression by inhibiting CDK7’s CAK activity. It effectively prevents activation of CDK1 and CDK2 without affecting RNA polymerase II transcription or superenhancer-associated genes. Treatment of murine SCLC models (Rb1L/Lp53L/Lp130L/L genetically engineered mouse models, RPP GEMMs) and established mouse SCLC RRP-MYC cells with CDK7 inhibitors and degraders results in reduced cell viability, accumulation of cells in the G1 phase, impaired DNA replication, increased DNA damage, and micronuclei formation, which can trigger immune responses.

Indeed, the series of events provoked by CDK7 inhibition in cancer cells trigger robust immune response signaling and secretion of pro-inflammatory factors, which potentiates T cell activity, resulting in tumor control. In murine SCLC models, these inhibitors/degraders were well-tolerated, significantly delayed tumor growth, and extended survival. When combined with anti-PD-1 immunotherapy, it achieved superior tumor inhibition compared to either agent alone. The combination therapy enhanced T cell activation and promoted a robust anti-tumor immune response.

Team Members: Nathanael S. Gray, PhD

Applications

• Enhancing the efficacy of immunotherapies like anti-PD-1 inhibitors in treating SCLC.

• Providing a new strategy to trigger anti-tumor immunity in patients unresponsive to current treatments.

• Combining with standard chemotherapy and immunotherapy to improve tumor responses and extend survival in SCLC patients.

Opportunities

Dana-Farber Cancer Institute is looking for the right partner with an interest in licensing these assets for further development as a therapeutic to benefit patients.

Team Members

Nathanael S. Gray, PhD

Professor of Chemical and Systems Biology, Co-Director of Cancer Drug Discovery, Stanford Medicine

Former Principal Investigator, Dana-Farber

Nathanael's Bio