Cyclin Based Inhibitors of CDK2 and CDK4
Structural and functional analysis of peptide inhibitor binding to the cyclin D and cyclin A groove has been investigated and used to design peptides that provide the basis for structure-activity relationships, have improved binding and have potential for development as chemical biology probes, as potential diagnostics and as therapeutics in the treatment of proliferative diseases including cancer and inflammation.
1 . A synthetic CDK/cyclin inhibitor that inhibits interaction of a complex formed between a first CDK protein and a first cyclin protein with a substrate of the complex, the synthetic CDK/cyclin inhibitor comprising 1-(3,5-dichlorophenyl)-5-methyl-1H-1,2,4-triazole carboxamide at the N-terminal, the inhibitor comprising βHomoLeu-NMethylPhe-NH 2 at the C-terminal, and the inhibitor comprising a linking group between the N-terminal and the C-terminal, the linking group comprising arginine or an arginine isostere.
2 . The synthetic CDK/cyclin inhibitor of claim 1 , wherein the linking group as the following structure:
wherein the R group is the arginine or the arginine isostere.
3 . The synthetic CDK/cyclin inhibitor of claim 2 , wherein the arginine isostere has one of the following structures:
4 . A synthetic CDK/cyclin inhibitor that inhibits interaction of a complex formed between a first CDK protein and a first cyclin protein with a substrate of the complex, the synthetic CDK/cyclin inhibitor being a derivative of a second CDK/cyclin inhibitor, the synthetic CDK/cyclin inhibitor comprising one or more substitutions and/or additions of an amino acid or a synthetic constituent as compared to the second CDK/cyclin inhibitor, the synthetic CDK/cyclin inhibitor having the following structure:
wherein
n1 is 1 or 0,
n2 is 1, 2, or 3,
the aromatic ring bonded to the (CH 2 ) n group can include one or more halogens on the ring,
R is hydrogen or ethyl.
5 . The synthetic CDK/cyclin inhibitor of claim 4 , wherein the inhibitor has one of the following structures:
n1 is 1, n2 is 1 and R is hydrogen;
n1 is 1, n2 is 1 and R is ethyl;
n1 is 1, n2 is 2 and R is hydrogen;
n1 is 1, n2 is 2 and R is ethyl;
n1 is 0, n2 is 3 and R is hydrogen; or
n1 is 1, n2 is 1 and R is ethyl.
6 . The synthetic CDK/cyclin inhibitor of claim 4 , wherein the inhibitor comprises either leucine or beta-leucine.
7 . A synthetic CDK/cyclin inhibitor that inhibits interaction of a complex formed between a first CDK protein and a first cyclin protein with a substrate of the complex, the synthetic CDK/cyclin inhibitor having the following structure:
wherein R1 is methyl or hydrogen and R2 has one of the two following structures:
8 . A synthetic CDK/cyclin inhibitor that inhibits interaction of a complex formed between a first CDK protein and a first cyclin protein with a substrate of the complex, the synthetic CDK/cyclin inhibitor having the following structure:
wherein
n1 is 0 or 1,
n2 is 3,
R1 is an arginine side chain,
R2 has one of the following structures:
R3, R4, and R5 are independently hydrogen or a halogen.
9 . The synthetic CDK/cyclin inhibitor of claim 8 , wherein the inhibitor is one of the following:
n1
n2
R2
R3
R4
R5
0 1
3 3
H H
H H
F F
0 1
3 3
H H
H H
F F
0 0 0 0
3 3 3 3
Cl H F H
H Cl H F
Cl H F H
10 . A synthetic CDK/cyclin inhibitor that inhibits interaction of a complex formed between a first CDK protein and a first cyclin protein with a substrate of the complex, the synthetic CDK/cyclin inhibitor is N-(5-guanidino-1-(naphthalen-2-ylamino)-1-oxopentan-2-yl)benzamide.
11 . A synthetic CDK/cyclin inhibitor that inhibits interaction of a complex formed between a first CDK protein and a first cyclin protein with a substrate of the complex, the synthetic CDK/cyclin inhibitor being a derivative of a second CDK/cyclin inhibitor, the synthetic CDK/cyclin inhibitor comprising one or more substitutions and/or additions of an amino acid or a synthetic constituent as compared to the second CDK/cyclin inhibitor, wherein the synthetic CDK/cyclin inhibitor includes a terminal C-cap that is not present on the second CDK/cyclin inhibitor, the terminal C-cap having the following structure:
wherein
n is 0 or 1
R1, R2, and R3 are independently hydrogen, isobutyl, methyl, ethyl, or propyl groups.
12 . The CDK/cyclin inhibitor of claim 11 , wherein the inhibitor is one of the following:
n
R1
R2
R3
0
iBut
iBut
H
0
iBut
iBut
H
0
Pr
iBut
H
0
Pr
iBut
Me
1
Me
iBut
H
1
Me
iBut
H
0
Et
iBut
H
0
Et
iBut
H
0
Me
iBut
H