Cyclin dependent kinase (CDK)4 inhibitors and their use for treating cancer
AssigneeThe Government of the United States of America
InventorsMichael J. Kelley, Kazuhiko Nakagawa, Barry Roy Dent
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Abstract
Certain derivatives of acridones and benzothiadiazines have been found to have anti-cancer properties by virtue of their specific inhibition of the cyclin D dependent kinase CDK4. These molecules inhibit CDK4 activity more than they inhibit the activity of other such kinases (e.g. CDC2 and CDK2). This specificity results in an improved therapeutic index when used as drugs to treat susceptible cancers.
Claims57
An antineoplastic composition comprising a therapeutically effective amount of a compound selected from the group consisting of 3-amino-10H-acridine-9-thione, 1,4-dimethoxy-10H-acridine-9-thione, 2,2′-biphenyldiamine, bis[N,N′-[3-(amido-N-methylamino)-10H-acridine-9-thione, 4-(4-fluorobenzylatino)-1,2,3-benzothiadiazine-1,1-dioxide, 3-chloro-4-methyl-4H-benzo[e][1,2,4]thiadiazine-1,1-dioxide, 3-chloro-4-ethyl-4H-benzo[e][1,2,4]thiadiazine-1,1-dioxide, and mixtures thereof, the compound or compounds having an IC50 for CDK4 of less than about 10 μM.
7 The antineoplastic composition of claim 6 wherein the compound further has an IC50 for CDK2/A of more than 100 μM.
The antineoplastic composition of claim 7 wherein the compound further has an IC50 for CDK2/E of more than about 100 μM.
An antineoplastic composition comprising a compound selected from the group consisting of 3-amino-10H-acridine-9-thione, 1,4-dimethoxy-10H-acridine-9-thione, 2,2′-biphenyldiamine, bis[N,N′-[3-(amido-N-methylamino)-10H-acridine-9-thione, 4-(4-fluorobenzylamino)-1,2,3-benzothiadiazine-1,1-dioxide, 3-chloro-4-methyl-4H-benzo[e][1,2,4]thiadiazine-1,1-dioxide, 3-chloro-4-ethyl-4H-benzo[e][1,2,4]thiadiazine-1,1-dioxide, and mixtures thereof, the compound or compounds having an IC50 ratio for CDC2:CDK4 of more than 8.5.
Antineoplastic compositions cormprisilng an effective amount of compounds having Formula 1
- 6
- Formula 1
- where M is 0 or 1, n=M, R1-R4 are independently selected from the group consisting of H, NH2, and methoxy, where with M=1 one of R1-R4 is an amine bonded to R1 to form an arylamide, or Formula 2
- 7
- where R and R1 are carbon or nitrogen, and with R1=carbon R1 is bonded to N1 by a double bond, R is nitrogen, X is hydrogen or halogen, and R2 is selected from the group consisting of alkyl and aryl amino, and mixtures of compounds having Formula 1 and/or Formula 2.
18 The composition according to claim 14 wherein the compound has an IC50 for CDK2/E of more than about 80 μM
A method for inhibiting the growth of living cells, comprising
- providing a compound selected from the group consisting of compounds having Formula 1
- 8
- where M is 0 or 1, n=M, R1-R4 are independently selected from the group consisting of H, NH2, and alkoxy, where with M=1 one of R1-R4 is an amine bonded to R1 to form an arylamide, or Formula 2
- 9
- where R and R1 are carbon or mutrogen, and with R1=carbon R1 is bonded to N1 by a double bond, R is nitrogen, X is hydrogen or halogen, and R2 is selected from the group consisting of alkyl and aryl amino, and mixtures of compounds having Formula 1 and/or Formula 2, the compound having an IC50 for CDK4 of less than about 10 μM, and having an IC50 for CDC2 of more than about 60 μM and having an IC50 for CDK2/A of more than about 100 μM, and having an IC50 for CDK2/E of more than about 80 μM;
- and
- administering an effective amount of the compound to inhibit the growth of living cells.
40 A method for inhibiting the growth of living cells, comprising
- providing a compound selected from the group consisting of compounds having Formula 1
- 10
- where M is 0 or 1, n=M, R1-R4 are independently selected from the group consisting of H, NH2, and alkoxy, where with M=1 one of R1-R4 is an amine bonded to R1 to form an arylamide, or Formula 2
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- Formula 2
- where R and R1 are carbon or nitrogen, and with R1=carbon R1 is bonded to N1 by a double bond and R is nitrogen, X is hydrogen or halogen, and R2 is selected from the group consisting of alcyl and aryl amino, and mixtures of compounds having Formula 1 and/or Formula 2, the compound having an IC50 ratio for CDC2:CDK4 of more than 8.5, and having an IC50 ratio for CDK2/A:CDK4 of more than about 14, and having an IC50 ratio for CDC2/E:CDK4 of more than about 11.5.
The method according to claim 40 where providing a compound comprises providing a composition comprising the compound and additives selected from the group consisting of carriers, diluents, excipients, diagnostics, direct compression buffers, buffers, stabilizers, fillers, disintegrates, flavors, colors, and mixtures thereof.
The method according to claim 40 where the compound is 2,2′-biphenyldiamine, bis[N,N′-[3-(amido-N-methylamino)-10H-acridine-9-thione.
The method according to claim 40 where, with respect to Formula 1, M=n=0.
The method according to claim 40 where, with respect to Formula 2, R is nitrogen.
The method according to claim 40 where the compound is
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The method according to claim 40 where the compound is
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The method according to claim 40 where the compound is
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Dependencies are inferred from the claim text.