Cdki pathway inhibitors and uses thereof
AssigneeSenex Biotechnology, Inc.
InventorsDonald C. Porter, Igor B. Roninson, Mark P. Wentland
Life of this patent
Estimating the term…
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.
Claims27
A compound represented by the structural formula:
- wherein R6 is selected from CN, F, Cl, Br, I, NO2, CF3, CHO, COR10, CO2R10, CONR11R12, C(═S)NR11R12, C(═NR10)NR11R12, SOR10, SO2R10 and SO2NR11R12,
- wherein R13 is 2-, 3-, or 4-H, F, Cl, Br, I, OH, OCH3, CH3, CF3, NR11R12, CH2R11R12, CO2H and CONR11R12;
- wherein R10 is H or C1-C6 alkyl, and each R11 and R12 is independently H or C1-C6 alkyl, or R11 and R12 taken together form a ring;
- provided however, that when R6 is F then R13 is not 4-OH or 4-Cl, when R6 is Cl then R13 is not 4-OH, 2-F, or 4-Cl, when R6 is Br then R13 is not H, 4-OH, 4-SO2NH2, 4-OCH3, 3-F, or 4-Cl, when R6 is I then R13 is not 3-F or 2-Cl, and when R6 is NO2 then R13 is not 3-F, 4-Cl, 4-Br, 4-I, 2-OCH3, 3-OCH3, 4-OCH3, 4-CONH2, 4-CON(CH3)2, or 4-CO2H.
A compound represented by the structural formula:
- wherein R6 is selected from CN, F, Cl, Br, I, NO2, CF3, CHO, COR10, CO2R10, CONR11R12, C(═S)NR11R12, C(═NR10)NR11R12, SOR10, SO2R10 and SO2NR11R12,
- wherein R13 is 2-, 3-, or 4-H, F, Cl, Br, I, OH, OCH3, CH3, CF3, NR11R12, CH2R11R12, CO2H and CONR11R12;
- wherein R10 is H or C1-C6 alkyl, and each R11 and R12 is independently H or C1-C6 alkyl, or R11 and R12 taken together form a ring.
A compound represented by the structural formula:
- wherein R6 is selected from CN, F, Cl, Br, I, NO2, CF3, CHO, COR10, CO2R10, CONR11R12, C(═S)NR11R12, C(═NR10)NR11R12, SOR10, SO2R10 and SO2NR11R12,
- wherein R13 is 2-, 3-, or 4-H, F, Cl, Br, I, OH, OCH3, CH3, CF3, NR11R12, CH2R11R12, CO2H and CONR11R12;
- wherein R10 is H or C1-C6 alkyl, and each R11 and R12 is independently H or C1-C6 alkyl, or R11 and R12 taken together form a ring.
A compound represented by the structural formula:
- wherein R6 is selected from CN, F, Cl, Br, I, NO2, CF3, CHO, COR10, CO2R10, CONR11R12, C(═S)NR11R12, C(═NR10)NR11R12, SOR10, SO2R10 and SO2NR11R12,
- wherein R13 is 2-, 3-, or 4-H, F, Cl, Br, I, OH, OCH3, CH3, CF3, NR11R12, CH2R11R12, CO2H and CONR11R12;
- wherein R10 is H or C1-C6 alkyl, and each R11 and R12 is independently H or C1-C6 alkyl, or R11 and R12 taken together form a ring;
- provided however, that when R6 is CHO then R13 is not H, when R6 is Cl then R13 is not 4-F or 4-OCH3, when R6 is Br then R13 is not H, 2-Cl, 4-Cl, 4-SO2NH2, 4-CO2H, 4-OCH3, or 4-CF3, when R6 is I then R13 is not H, 2-CF3 or 3-CF3, and when R6 is NO2 then R13 is not H or 4-Cl.
A compound represented by the structural formula:
- wherein R6 is selected from CN, F, Cl, Br, I, NO2, CF3, CHO, COR10, CO2R10, CONR11R12, C(═S)NR11R12, C(═NR10)NR11R12, SOR10, SO2R10 and SO2NR11R12;
- wherein R10 is H or C1-C6 alkyl, and each R11 and R12 is independently H or C1-C6 alkyl, or R11 and R12 taken together form a ring.
A compound represented by the structural formula:
- wherein R6 is selected from F, Br, I, NO2, CF3, COR10, CO2R10, CONR11R12, C(═S)NR11R12, C(═NR10)NR11R12, SOR10, SO2R10 and SO2NR11R12;
- wherein R10 is H or C1-C6 alkyl, and each R11 and R12 is independently H or C1-C6 alkyl, or R11 and R12 taken together form a ring.
A compound represented by the structural formula:
- wherein R6 is selected from CN, F, Cl, NO2, CF3, CHO, COR10, CO2R10, CONR11R12, C(═S)NR11R12, C(═NR10)NR11R12, SOR10, SO2R10 and SO2NR11R12;
- wherein R10 is H or C1-C6 alkyl, and each R11 and R12 is independently H or C1-C6 alkyl, or R11 and R12 taken together form a ring.
A compound represented by the structural formula:
- wherein R6 is selected from CN, F, Cl, Br, I, NO2, CF3, CHO, COR10, CO2R10, CONR11R12, C(═S)NR11R12, C(═NR10)NR11R12, SOR10, SO2R10 and SO2NR11R12;
- wherein R13 is 2-, 3-, or 4-H, F, Cl, Br, I, OH, OCH3, CH3, CF3, NR11R12, CH2R11R12, CO2H and CONR11R12;
- wherein R10 is H or C1-C6 alkyl, and each 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;
- provided however that when R6 is Br, I or NO2 then R13 is not H.
A compound represented by the structural formula:
- wherein R6 is selected from CN, F, Cl, Br, I, NO2, CF3, CHO, COR10, CO2R10, CONR11R12, C(═S)NR11R12, C(═NR10)NR11R12, SOR10, SO2R10 and SO2NR11R12;
- wherein R13 is 2-, 3-, or 4-H, F, Cl, Br, I, OH, OCH3, CH3, CF3, NR11R12, CH2R11R12, CO2H and CONR11R12;
- wherein R10 is H or C1-C6 alkyl, and each 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.
A compound represented by the structural formula:
- wherein each of X1, X2 and X3 is independently N or CH, and one, but only one, of X1, X2 and X3 is N;
- wherein R6 is selected from CN, F, Cl, Br, I, NO2, CF3, CHO, COR10, CO2R10, CONR11R12, C(═S)NR11R12, C(═NR10)NR11R12, SOR10, SO2R10 and SO2NR11R12;
- wherein R13 is 2-, 3-, or 4-H, F, Cl, Br, I, OH, OCH3, CH3, CF3, NR11R12, CH2R11R12, CO2H and CONR11R12;
- wherein R10 is H or C1-C6 alkyl, and each 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;
- provided however, that when X1 is N and n=1, then R6 is not Br, when X2 is N and n=1 then R6 is not Br, I or CHO and when X3 is N and n=1 then R6 is not Br or CHO.
A compound represented by a structural formula selected from the structural formulae shown in FIG. 1 or FIG. 2.
A method for enhancing induction of G1 cell cycle arrest by CDKI proteins comprising contacting a cell with a compound having the structure (VI):
- wherein R4 is selected from C1-C6 alkyl and C1-3—R14, wherein R14 is a 6 membered aryl or heteroaryl group or a fused bicyclic aryl or heteroaryl group, either of which may be optionally substituted with one or more substituent selected from 2-, 3-, or 4-H, F, Cl, Br, I, OH, OCH3, CH3, CF3, NR11R12, CH2R11R12, CO2H and CONR11R12, and wherein R6 is an electron withdrawing group.
A method for inhibiting the production of tumor-promoting secreted factors by fibroblasts, comprising contacting the tumor-associated fibroblast with a compound having the structure (VI):
- wherein R4 is selected from C1-C6 alkyl and C1-3—R14, wherein R14 is a 6 membered aryl or heteroaryl group or a fused bicyclic aryl or heteroaryl group, either of which may be optionally substituted with one or more substituent selected from 2-, 3-, or 4-H, F, Cl, Br, I, OH, OCH3, CH3, CF3, NR11R12, CH2R11R12, CO2H and CONR11R12, and wherein R6 is an electron withdrawing group.
A method for therapeutically treating a mammal having a CDKI-mediated disease comprising administering to the mammal a therapeutically effective amount of a compound having the structure (VI):
- wherein R4 is selected from C1-C6 alkyl and C1-3—R14, wherein R14 is a 6 membered aryl or heteroaryl group or a fused bicyclic aryl or heteroaryl group, either of which may be optionally substituted with one or more substituent selected from 2-, 3-, or 4-H, F, Cl, Br, I, OH, OCH3, CH3, CF3, NR11R12, CH2R11R12, CO2H and CONR11R12, and wherein R6 is an electron withdrawing group.
A method for therapeutically treating a mammal infected with HIV comprising administering to the mammal a therapeutically effective amount of a CDKI pathway inhibitor.
A compound that inhibits CDK8 to a greater extent than it inhibits CDK1, CDK2, CDK4 and CDK6 and further inhibits CDK8 to a greater extent than ROCK2, provided that the compound does not have a structure shown in FIG. 6.
Dependencies are inferred from the claim text.