Quinoline-based compounds and methods of inhibiting CDK8/19
Inventors
Roninson, Igor • McInnes, Campbell • Chen, Mengqian • Zhang, Li • Li, Jing
Assignees
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Publication Number
US-11014906-B2
Publication Date
2021-05-25
Expiration Date
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 patent describes quinoline-based CDK8/CDK19 inhibitor compounds defined by Formula I, with substituents at quinoline positions 4 and 6 and detailed R1, R2, R3, and R4 selections. The compounds include halogen, —CN, —NO2, amino, trifluoromethyl, —R, —OR, —SR, —RNR′R″, and multiple sulfonyl, phosphoryl, carbonyl, and amide-like motifs, together with ring-closure rules and conditional constraints for substituents on the same nitrogen atom.
The described compounds are presented as CDK8 or CDK19 inhibitors and as a family intended for modulation of CDK8-associated and/or CDK19-associated biological states. The document also provides specific embodiment structures through Formula IA, Formula IB, and Formula IC and their labeled variants, while maintaining the same core Formula I substituent framework.
The invention further includes methods for inhibiting CDK8 or CDK19 by contacting CDK8 or CDK19 with an effective amount of a compound of Formula I. It also includes methods for treating a subject having a CDK8-associated disease, disorder, or condition or a CDK19-associated disease, disorder, or condition by administering a pharmaceutical composition comprising a therapeutically effective amount of the compound, with selectivity language relative to a panel of other CDKs.
Claims Coverage
The independent claims identified center on a Formula I quinoline-based compound, a method for treating CDK8- or CDK19-associated disease or condition, and a method for inhibiting CDK8 or CDK19. The inventive scope is defined by the R1/R2/R3/R4 substituent framework, and for inhibition, by an at-least 2-fold greater effect on CDK8 and/or CDK19 than on a defined panel of other CDKs.
Formula I quinoline-based compound with defined substituents
A compound of Formula I wherein R1 is selected from a halogen, —CN, —NO2, amino, or trifluoromethyl; R2 is selected from detailed substituent options; R3 comprises a substituted or unsubstituted, branched or unbranched C1-C6 alkylene; and R4 is selected from halogen, —CN, —NO2, —R, —OR, —SR, —RNR′R″, and sulfonyl, phosphoryl, carbonyl, and amide-like groups, with independently selected R, R′, and R″ substituents and ring-closure rules.
Treatment of CDK8-associated or CDK19-associated disease using a therapeutically effective pharmaceutical composition
A method for treatment of a subject having a CDK8-associated disease, disorder, or condition or a CDK19-associated disease, disorder, or condition comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a Formula I compound having the same structured substituent selection framework, with the treated condition optionally selected from breast cancer, prostate cancer, or kidney cancer.
Selective inhibition of CDK8 and/or CDK19
A method for inhibiting CDK8 or CDK19 by contacting CDK8 or CDK19 with an effective amount of a Formula I compound, wherein the extent of inhibition of CDK8 and/or CDK19 is at least 2-fold more than the extent of inhibition of CDK2, CDK3, CDK4, CDK5, CDK7, CDK9, CDK11A, CDK11B, CDK13, CDK14, CDK15, CDK16, CDK17, CDK18, CDKL1, CDKL3, or CDKL5.
Overall, the claims define a Formula I quinoline-based compound family by detailed substituent selections and associate that family with treatment of CDK8- or CDK19-associated diseases and selective inhibition of CDK8 and/or CDK19 against other CDKs.
Stated Advantages
Improved kinase selectivity as reported by DiscoverX Kd measurements, with strong binding to CDK19 and CDK8 and markedly weaker binding to HASPIN, MAP4K2, and MYO3B.
Demonstrated CDK8/19-dependent inhibition of NFκB-associated MYC, CXCL1, and IL8 responses in cell-based assays.
Improved duration characterized by wash-off retention after 2 h.
Reduced hepatocyte metabolic conversion and longer mouse half-life.
Improved oral exposure and increased tumor tissue levels.
In vivo anti-cancer effects including reduced PSA and AR-inducible gene expression in castration-refractory prostate cancer xenografts and increased survival in a metastatic TNBC model.
Inhibition selectivity is claimed via an at least 2-fold greater extent of inhibition of CDK8 and/or CDK19 than inhibition of a specified panel of other CDKs.
Documented Applications
Treatment of castration-refractory prostate cancer using described in vivo xenograft outcomes including reduced PSA and AR-inducible gene expression.
Treatment of metastatic TNBC using a described metastatic model with increased survival.
Inhibition/targeting of CDK8 or CDK19 in cell-based assays demonstrating inhibition of MYC, CXCL1, and IL8 that is dependent on CDK8/19.
Treatment of a subject having a CDK8-associated disease, disorder, or condition or a CDK19-associated disease, disorder, or condition.
Inhibition of CDK8 or CDK19 by contacting CDK8 or CDK19 with an effective amount of a Formula I compound.
The CDK8-associated or CDK19-associated disease, disorder, or condition is selected from breast cancer, prostate cancer, or kidney cancer.
Cancer and inflammation-related conditions.
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