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Publication Number
US-12678438-B2
Publication Date
2026-07-14
Expiration Date
Abstract
The present invention relates to methods of treating cancer by administration of a cyclin dependent kinase (CDK) inhibitor to a subject.
Core Innovation
The invention relates to treating an androgen receptor (AR)-dependent cancer, wherein the cancer is prostate cancer, by administering an inhibitor of cyclin dependent kinase 7 (CDK7) or a corresponding pharmaceutical composition to a human subject in need thereof. CDK7 is described as phosphorylating MED1 at Thr1457 (T1457), enabling MED1-AR complex formation at super-enhancers and AR-dependent transcriptional addiction in castration-resistant prostate cancer (CRPC).
MED1 is described as being recruited together with AR to super-enhancers, with DHT increasing AR and MED1 co-occupancy at super-enhancers. MED1 knockdown reverses DHT transcriptional programs without altering AR levels, supporting a MED1-dependent mechanism for AR transcriptional amplification, and pharmacologic CDK7 inhibition blocks MED1/AR co-recruitment genome-wide and suppresses AR target gene expression.
The disclosure further describes MED1 phosphorylation at T1457 and T1032 as ligand-dependent, with nuclear phosphorylated MED1 (p-MED1) linked to prostate cancer relevance and prognostic context across benign to metastatic tissue. CDK7 inhibition or CDK7 knockdown abolishes p-MED1, disrupts MED1/AR chromatin recruitment and AR target gene expression, and reverses features of enzalutamide resistance while inhibiting tumor growth in AR-positive prostate cancer models, including xenografts.
Claims Coverage
The independent claim covers treatment of an androgen receptor (AR)-dependent cancer by administering an effective amount of a CDK7 inhibitor or corresponding pharmaceutical composition to a human subject, where the cancer is prostate cancer. The claims add 5 inventive features centered on CRPC, example CDK7 inhibitors, anti-androgen resistance, outcome-related markers, and administration routes.
Treating AR-dependent prostate cancer with a CDK7 inhibitor
A method for treating an androgen receptor (AR)-dependent cancer by administering an effective amount of an inhibitor of cyclin dependent kinase 7 (CDK7) or a corresponding pharmaceutical composition to a human subject in need thereof, wherein the AR-dependent cancer is prostate cancer.
Treating castration resistant prostate cancer
The method in which the prostate cancer is castration resistant prostate cancer (CRPC).
Using a CDK7 inhibitor selected from listed candidates
The method in which the CDK7 inhibitor is selected from THZ1, SY-5609, CT7001, seliciclib, TG-02, PHA-793887, SY-351, roniciclib, SNS-032, BS-181L, and BS-194.
Treating an AR-dependent cancer in an anti-androgen resistant subject
The method in which the subject is resistant to anti-androgen therapy.
Achieving tumor volume reduction and biomarker changes including p-MED1
A method in which administering a CDK7 inhibitor or a pharmaceutical composition thereof results in reductions in tumor volume and plasma PSA expression, loss of PSA expression, decreased proliferative activity, increased apoptosis and necrosis, and a reduction in p-MED1 levels in the tumor.
Oral or intravenous administration of the composition
The method includes administering a composition by oral administration or by intravenous injection.
The claims center on treatment of AR-dependent prostate cancer using a CDK7 inhibitor or corresponding pharmaceutical composition, narrowed to CRPC and anti-androgen resistant subjects. The dependent claims further recite oral or intravenous administration, example inhibitors, and outcome-associated markers including reductions in tumor volume, PSA expression changes, and p-MED1 levels.
Stated Advantages
Reduces tumor volume.
Reduces plasma PSA expression and results in loss of PSA expression.
Decreases proliferative activity.
Increases apoptosis and necrosis.
Reduces p-MED1 levels in the tumor.
Suppresses AR target gene expression, including inhibition of PSA and ERG.
Reverses features of enzalutamide resistance.
Inhibits tumor growth in AR-positive prostate cancer models, including xenografts.
Reduces AR/MED1 co-recruitment genome-wide via CDK7 inhibition.
Provides biomarker/prognostic context using nuclear p-MED1.
Documented Applications
Treating an androgen receptor (AR)-dependent cancer, wherein the AR-dependent cancer is prostate cancer, including castration resistant prostate cancer (CRPC) and subjects resistant to anti-androgen therapy.
Treating AR-dependent prostate cancer in a human subject, including prostate cancer where CDK7 inhibition is described in relation to AR-dependent transcriptional addiction in CRPC.
Preclinical tumor growth inhibition in AR-positive prostate cancer models, including xenograft mouse models.
Contextual use of nuclear p-MED1 as a biomarker/prognostic marker in prostate cancer.
Combination treatment context involving CDK inhibition with anti-androgen therapy.
Clinical and biological outcome-associated use cases described in the partial content include reductions in tumor volume, changes in PSA expression, increased apoptosis and necrosis, and reduction of p-MED1 levels in tumor contexts, including models described as enzalutamide-resistant.
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