CDK8-CDK19 selective inhibitors and their use in anti-metastatic and chemopreventative methods for cancer
Inventors
Roninson, Igor B • Porter, Donald C
Assignees
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Publication Number
US-10993945-B2
Publication Date
2021-05-04
Expiration Date
Abstract
The invention relates to the compounds and methods for inhibiting the Cyclin-Dependent Kinase Inhibitor (CDKI) pathway. More particularly, the invention relates to compounds and methods for inhibiting the CDKI pathway for studies of and intervention in senescence-related and other CDKI-related diseases. The invention provides new compounds having improved solubility and/or potency, and methods for their use. In various aspects, the invention relates to the treatment of cancer. The invention provides methods for chemoprevention and prevention of tumor recurrence or metastasis. The invention further provides diagnostic techniques for treatment for certain cancer types. The invention utilizes specific inhibitors of CDK8/19 and/or measurement of CDK8 levels in a patient.
Core Innovation
The invention relates to CDK8/CDK19 pathway inhibition using a small molecule compound that specifically inhibits CDK8/19. The disclosed approach suppresses tumor-promoting factors mediated by NF-κB and is linked to downstream pathway suppression including Wnt/β-catenin pathway suppression and effects on β-catenin-dependent TOPFLASH promoter activity.
The invention addresses preventing breast cancer recurrence or metastasis in a breast cancer patient after debulking by administering the CDK8/19 specifically inhibiting small molecule compound following debulking. It further describes preventing tumor invasion in a breast cancer patient by administering the small molecule compound that specifically inhibits CDK8/19.
The disclosed scope includes methods for treating breast cancer by administering a CDK8/19 specifically inhibiting small molecule compound, including in combination with a DNA damaging agent. The document additionally provides diagnostic/prognostic guidance using CDK8, and optionally CDK19/CCNC/CXCL1/2, expression levels to identify patients likely to benefit from DNA damaging agents or adjuvant therapy.
Claims Coverage
The provided claim set includes four independent claims. Across these claims, the main inventive focus is the administration of a small molecule compound that specifically inhibits CDK8/19, with claims directed to post-debulking recurrence/metastasis prevention, tumor invasion prevention, and treatment alone or in combination with a DNA damaging agent.
Post-debulking CDK8/19 inhibition for recurrence/metastasis prevention
Administering to a breast cancer patient after debulking a small molecule compound that specifically inhibits CDK8/19 following debulking.
CDK8/19 inhibition for tumor invasion prevention
Administering to a breast cancer patient a small molecule compound that specifically inhibits CDK8/19 to prevent tumor invasion.
CDK8/19 inhibition combined with a DNA damaging agent for treatment
Administering to a breast cancer patient a small molecule compound that specifically inhibits CDK8/19 in combination with a DNA damaging agent.
CDK8/19 inhibition as a standalone treatment for breast cancer
Administering to a patient a small molecule compound that specifically inhibits CDK8/19 to treat breast cancer.
Collectively, the independent claims center on using a small molecule compound that specifically inhibits CDK8/19, either as a stand-alone therapy for breast cancer or as part of combination therapy with a DNA damaging agent, and also as a targeted strategy to prevent tumor invasion and to prevent recurrence/metastasis after debulking.
Stated Advantages
Prevents breast cancer recurrence or metastasis after debulking.
Prevents tumor invasion.
Treats breast cancer.
Provides treatment in combination with a DNA damaging agent.
Identifies patients likely to benefit from DNA damaging agents or adjuvant therapy using CDK8 and optionally CDK19/CCNC/CXCL1/2 expression levels.
Documented Applications
Preventing breast cancer recurrence or metastasis in a breast cancer patient who has undergone debulking treatment.
Preventing tumor invasion in a breast cancer patient.
Treating a breast cancer patient with CDK8/19-specific inhibition in combination with a DNA damaging agent.
Treating breast cancer in a patient with CDK8/19-specific inhibition.
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