CDKI pathway inhibitors and uses thereof
Inventors
Porter, Donald C. • Roninson, Igor B. • Wentland, Mark P.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-8598344-B2
Publication Date
2013-12-03
Expiration Date
Abstract
The invention relates to compounds for inhibiting the Cyclin-Dependent Kinase Inhibitor (CDKI) pathway. More particularly, the invention relates to compounds for inhibiting the CDKI pathway for studies of and intervention in senescence-related and other CDKI-related diseases.
Core Innovation
The patent describes a CDKI pathway inhibitor approach focused on blocking transcriptional induction downstream of CDKI proteins. The invention is directed to SNX2-class small molecules whose scaffold definitions and substituent constraints define the claimed chemical space.
The background problem described is that CDKI pathway activation contributes to senescence programs, including senescence and senescent morphology development, which are connected to senescence-related diseases. The document discusses senescence-related disease areas such as Alzheimer’s/amyloidosis, atherosclerosis, arthritis, and chronic renal disease, and also addresses cancer settings involving paracrine tumor-promoting fibroblast secretions and viral diseases, including HIV.
The compound concept emphasizes inhibition of CDK8 and, optionally, CDK19 as the key downstream effect in the described pathway context. The disclosed scaffold formulas, including I-A/I-B/I-C, II-A/II-B/II-C, III, IV-A/IV-B, V, and VI, use explicit substituent definitions and exclusion rules to support transcriptional effects and downstream functional outcomes in the disclosed assay contexts.
Claims Coverage
The partial independent claim set provided centers on a single independent claim defining a compound by a structural formula with substituent constraints, including a fixed R6 substituent, a defined R13 selection set, and constraints on R11 and R12 including an alternative ring-forming relationship. Dependent claims refine the R13 selection and the relationship between R11 and R12.
SNX2-class compound structural formula with constrained substituents
A compound represented by a structural formula wherein R6 is CN; wherein R13 is selected from the group consisting of 2-, 3-, or 4-H, F, Cl, Br, I, OH, OCH3, CH3, CF3, NR11R12, CH2R11R12, CO2H and CONR11R12; and each R11 and R12 is independently H or C1-C6 alkyl, or R11 and R12 taken together form a ring.
Across the dependent claims in the provided material, the main inventive structure is narrowed primarily by selecting specific members of the R13 group, including Cl, H, and CONR11R12, and by specifying that R11 and R12 together form a ring.
Stated Advantages
Little or no cytotoxicity in normal cells.
Does not interfere with CDKI-mediated G1 arrest and can enhance G1 arrest.
Blocks senescent morphology development in DNA-damage-arrested fibroblasts.
Reduces secretion of anti-apoptotic and tumor-promoting factors.
Documented Applications
Treatment or modulation of senescence-related disease contexts discussed in the document, including Alzheimer’s/amyloidosis, atherosclerosis, arthritis, and chronic renal disease.
Cancer-related use context involving paracrine tumor-promoting fibroblast secretions.
Viral disease context including HIV.
Interested in licensing this patent?