CDK8-CDK19 selective inhibitors and their use in anti-metastatic and chemopreventative methods for cancer
Inventors
Roninson, Igor B • Porter, Donald C • 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-9321737-B2
Publication Date
2016-04-26
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-selective small-molecule inhibitors defined by a structural formula I or II. The compounds include substituent variables B, D, and a parameter n, with each B independently hydrogen or a provided option, at least one B being hydrogen, not more than one B being hydrogen, D selected from —NH, —N-lower alkyl, or O, and n being 0-2.
The core definition provides a constrained structure for the small molecules while maintaining a range of allowable substituents through B, D, and n. The document describes exemplary compounds within this structural formula framework, including SNX2-1-162 to SNX2-1-167, with emphasis on SNX2-1-165 (Senexin B). Selectivity and potency are reported for CDK8/CDK19 pathway inhibition.
The disclosed compounds are used in therapeutic and diagnostic contexts in cancer, including chemoprevention and prevention of tumor recurrence and metastasis after debulking. Additional uses include treatment of β-catenin-expressing tumors and combination or adjuvant therapy settings involving DNA-damaging agents, together with patient selection and recurrence-risk assessment based on CDK8 overexpression and optionally additional marker overexpression.
Claims Coverage
The independent claim covers small-molecule compounds defined by structural formula I or II with constraints on B, D, and n, and specifies CDK8/CDK19-selective inhibitors within that structural scope. The claim set includes multiple dependent refinements that further narrow the substituent definitions and parameter values.
Structural formula I or II small-molecule definition
A small molecule compound having a structural formula I or II, wherein each B is independently hydrogen or [provided option], with at least one B being hydrogen and not more than one B being hydrogen, D is selected from —NH, —N-lower alkyl, or O, and n is 0-2.
Methyl as the lower alkyl substituent
The compound of the preceding structural formula definition wherein the lower alkyl group is methyl.
Parameter n constrained to 0 or 1
The compound of the preceding structural formula definition wherein n is either 0 or 1.
Parameter n constrained to 1
The compound of the preceding structural formula definition wherein n equals 1.
Specific structural-formula depiction
A small molecule compound defined by the structural formula shown for the compound of the preceding structural formula definition.
Compound tied to specific structural-formula representations in associated files
A small molecule compound defined by the structural formula shown for the compound of the preceding structural formula definition, with the definition tied to specific structural-formula representations provided in associated image/file formats.
Overall, the claims define a structurally constrained CDK8/CDK19-selective small-molecule inhibitor scaffold (structural formula I or II) by limiting B, D, and n, and they further narrow the scaffold by dependent constraints such as methyl as the lower alkyl group and specific allowed n values, as well as by referencing specific structural formula depictions/representations.
Stated Advantages
CDK8/CDK19 pathway inhibition with reported selectivity and potency.
Improved solubility and bioavailability are reported.
In vivo reduction of subsequent tumor growth is reported.
Inhibition of β-catenin transcriptional activity is reported.
Patient selection/recurrence risk assessment based on CDK8 overexpression is described.
Documented Applications
Chemoprevention.
Prevention of tumor recurrence and metastasis after debulking.
Treatment of β-catenin-expressing tumors.
Combination therapy with DNA-damaging agents, including doxorubicin or platinum compounds.
Adjuvant therapy.
Patient selection and recurrence-risk assessment by measuring CDK8 overexpression, with optional measurement of CCNC, CDK19, CXCL1, and CXCL2 overexpression.
Interested in licensing this patent?