Quinoline-based compounds and methods of inhibiting CDK8/19
Inventors
Roninson, Igor • McInnes, Campbell • Chen, Mengqian • Zhang, Li • Li, Jing
Assignees
University of South Carolina • Senex Biotechnology Inc
Publication Number
US-12281080-B2
Publication Date
2025-04-22
Expiration Date
2039-08-21
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Abstract
Disclosed herein are quinoline-based compounds and method for inhibiting CDK8 or CDK19 for the intervention in diseases, disorders, and conditions. The quinoline-based composition comprise substituents at quinoline ring positions 4 and 6, wherein the substituent at position 4 is selected from a substituted or unsubstituted arylalkylamine or a substituted or unsubstituted arylhetrocyclylamine. Pharmaceutical compositions comprising the substituted quinoline compositions, methods of inhibiting CDK8 or CDK19, and methods of treating CDK8/19-associated diseases, disorders, or conditions are also disclosed.
Core Innovation
The invention provides quinoline-based compounds with specific substituents at the 4 and 6 positions of the quinoline ring for the inhibition of CDK8 and CDK19 kinases. These compounds feature a substituent at position 4 selected from substituted or unsubstituted arylalkylamine or arylhetrocyclylamine, and various potential substituents at position 6. The patent describes detailed chemical structures, including formulas, synthetic routes, and key variants such as Senexin C and its related derivatives, and their use as potent CDK8/19 inhibitors.
The background section identifies the problem that, despite previous development of CDK8/19 inhibitors, none have been approved for clinical use. Existing inhibitors such as quinazoline-based compounds exhibit limitations in potency, selectivity, and pharmacokinetic properties. There is a need for novel CDK8/19 inhibitors with improved efficacy, target selectivity, and pharmacokinetic behavior.
This invention addresses these issues by providing new quinoline-based compounds that demonstrate high selectivity and potency for inhibiting CDK8 and CDK19, as evidenced by cell-free and cell-based assays. These compounds, including pharmaceutical compositions thereof, display improved pharmacokinetic properties, longer duration of action, and increased metabolic stability compared to quinazoline analogs. Methods of treatment and inhibition using these compositions for diseases, disorders, and conditions associated with CDK8/19 activity are also disclosed.
Claims Coverage
There are three independent claims covering inventive features related to specific quinoline-based chemical compounds, methods of treating certain cancers, and methods for CDK8/19 inhibition.
Quinoline-based compound of Formula 1B
A compound characterized by the structure of Formula 1B as defined in the patent. The inventive feature includes: - Substituted quinoline core with defined R1, R3, and R4 groups. - R4 includes specified moieties such as —N(RC)— or —S(=O)(=NRD)—, where RC or RD can be defined alkyl, oxo-substituted, hydroxyl-substituted, or amino-substituted groups. - RA and RB in R4 can be independently substituted or unsubstituted alkyls, cycloalkyls, phenyls, heterocyclic or heteroaryl groups, or form certain rings as described.
Method for the treatment of breast cancer or prostate cancer using the claimed pharmaceutical composition
A method involving: - Administering a pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula 1B (as claimed above). - Explicitly indicated for the treatment of a subject having breast cancer or prostate cancer.
Method for the inhibition of CDK8 or CDK19 using the claimed compound
A method involving: - Contacting CDK8 or CDK19 with an effective amount of the compound of Formula 1B. - The claim specifies inhibition of CDK8 or CDK19 by the defined compound.
The claims cover the novel class of quinoline-based CDK8/19 inhibitor compounds, their pharmaceutical use in treating breast or prostate cancer, and their use for targeted inhibition of CDK8 or CDK19 kinases.
Stated Advantages
The disclosed compounds show improved potency in cell-based assays compared to previously described quinazoline-based analogs.
The quinoline-based inhibitors provide longer duration of CDK8/19 inhibition in target cells.
Quinoline-based compounds demonstrate increased metabolic stability relative to quinazoline analogs.
These compounds exhibit improved pharmacokinetic properties, including increased half-life and lower elimination rate.
The compounds maintain high target selectivity for CDK8/19 over other CDK family kinases.
Documented Applications
Treatment of diseases, disorders, or conditions associated with CDK8 or CDK19 activity, including cancer, inflammation-associated diseases, cardiovascular diseases, ribosomopathies, conditions with reduced hematopoietic stem cells and/or progenitor cells, and bone anabolic disorders.
Methods of inhibiting CDK8 or CDK19 in vitro or in vivo using the disclosed quinoline-based compounds.
Treatment of breast cancer or prostate cancer in a subject by administering the pharmaceutical composition containing the claimed compound.
Use in cell-based assays for inhibiting expression of MYC, NFκB-inducible genes (such as CXCL1, IL8), and PSA in relevant cell lines.
Suppression of metastasis in cancers, exemplified by use in breast cancer models to increase survival after tumor removal.
Inhibition of CDK8/19-dependent gene expression and cell proliferation in leukemia cell models (MV4-11, HL60).
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