CDKI pathway inhibitors and uses thereof
Inventors
Porter, Donald C • Roninson, Igor B • WENTLAND, Mark P
Assignees
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Publication Number
US-9409873-B2
Publication Date
2016-08-09
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.
Core Innovation
The invention relates to inhibition of the CDKI pathway in diseases associated with cellular senescence and other CDKI-mediated diseases. SNX2-class small molecules inhibit transcriptional induction downstream of CDKIs, and the disclosed approach is framed as targeting the mediator complex in which CDK8 acts as the pathway mediator.
The SNX2-class small molecules are characterized by little or no cytotoxicity in normal cells and do not interfere with CDKI cell-cycle arrest while enhancing G1 arrest induction. The compounds also block senescent fibroblast morphology and reduce fibroblast secretion of tumor-promoting anti-apoptotic factors.
The document further describes preferential inhibition of CDK8 over other CDKs and over ROCK2, and supports the role of CDK8 as the mediator of CDKI pathway activity by stating that CDK19 knockdown does not reduce IPTG/p21-driven CMV-GFP expression. Broad compound coverage is provided through multiple structural formulas with substituent definitions and constraints, including n from 1 to 3.
The partial content also describes the functional impact of the disclosed compounds on transcriptional induction driven by p21, inhibition of HIV-1 replication, kinase selectivity correlations using KinomeScan/KinaseProfiler, and limited endothelial proliferation effects compared with cortistatin A. Additional described biological contexts include inhibition of colon carcinoma cell growth, particularly β-catenin-sensitive lines.
Claims Coverage
The relevant independent claim contains a compound definition by a structural formula with multiple substituent constraints, including R6=CN, R13=CONR11R12, independent selection of R11 and R12 or their combination to form a ring, and a range for n from 1 to 3. The dependent claims mainly narrow structural constraints by specifying ring formation and fixing n to a single value.
Compound structural formula with defined substituents
A compound represented by the structural formula wherein R6 is CN, R13 is CONR11R12, each of R11 and R12 is independently H or C1–C6 alkyl, or R11 and R12 taken together form a ring, and wherein n is from 1–3.
Ring-forming substituents R11 and R12
The compound characterized such that R11 and R12 are taken together to form a ring.
Fixed parameter n
The compound specified to have n equal to 2.
Overall, claim coverage centers on a SNX2-class small-molecule structural framework with a defined core substituent pattern (R6=CN and R13=CONR11R12), optional ring formation via R11/R12 together, and a parameter n constrained to 1–3 in the independent claim and fixed to 2 in a dependent claim.
Stated Advantages
Little or no cytotoxicity in normal cells.
Does not interfere with CDKI cell-cycle arrest.
Enhances G1 arrest induction.
Blocks senescent fibroblast morphology.
Reduces fibroblast secretion of tumor-promoting anti-apoptotic factors.
Documented Applications
Inhibition of senescence-related and other CDKI-mediated diseases, including Alzheimer’s disease/dementias and amyloidosis.
Inhibition of cancer, including colon carcinoma cell growth, particularly β-catenin-sensitive lines.
Treatment or inhibition of viral disease, described with inhibition of HIV-1 replication.
Inhibition/impact on atherosclerosis.
Inhibition/impact on arthritis.
Inhibition/impact on chronic renal disease.
Modulation of senescent fibroblast paracrine activity by suppressing protective effects from senescent fibroblasts.
Effects compared in endothelial proliferation assays versus cortistatin A.
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