Small Molecule Choline Kinase Inhibitors, Screening Assays, and Methods for Safe and Effective Treatment of Neoplastic Disorders
OwnerBrian Clem, Sucheta Telang +4inventors
InventorsBRIAN CLEM, SUCHETA TELANG, JOHN TRENT, JASON CHESNEY, POORAN CHAND, GILLES TAPOLSKY
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Abstract
Small molecule choline kinase inhibitors, pharmaceutical compositions thereof, and screening methods for identifying and evaluating choline kinase inhibitors are provided. Safe and effective methods for treating subjects suffering from a disorder or disease characterized by neoplastic cell proliferation employing the choline kinase inhibitors are also provided.
Claims21
A method of treating a subject suffering from a disorder or disease characterized by neoplastic cell proliferation, the method comprising administering to the subject a therapeutically effective amount of a selective choline kinase (ChoK) inhibitor, wherein the ChoK inhibitor is selected from compounds having the following structural formula:
- wherein Het can be a substituted or unsubstituted bivalent heterocyclic group, L1 can be a bond, or substituted or unsubstituted bivalent C1-C2 alkane, L1 can be straight-chained or branched-chain, L2 can be a substituted or unsubstituted bivalent C3-C5 alkane, where one or more of the carbons of the bivalent C3-C5 alkane can be replaced with one or more heteroatoms, such as N, S, O, or P;
- L2 can be straight-chained or branched-chain;
- A1 and A2 can be the same or different and can be substituted or unsubstituted aryl groups or substituted or unsubstituted aromatic heterocyclic groups;
- or
- wherein L3 can be a substituted or unsubstituted bivalent C1-C3 alkane, where one or more of the carbons of the bivalent C1-C3 alkane can be replaced with one or more heteroatoms, such as N, S, O, or P, and L3 can be straight-chained or branched-chained;
- L4 can be a substituted or unsubstituted bivalent C1-C4 alkane, where one or more of the carbons of the bivalent C1-C4 alkane can be replaced with one or more heteroatoms, such as N, S, O, or P;
- L4 can be straight-chained or branched-chained;
- A3 and A4 can be the same or different and can be substituted or unsubstituted aryl groups or substituted or unsubstituted aromatic heterocycle groups (e.g., univalent radicals of indole, benzofuran, benzothiophene, naphthalene, quinoline, pyridine, or thiophene);
- L5 can be the substituted or unsubstituted bivalent
- where X1 can be C, or N, S, O, or P;
- and X2 can be N, S, O, P, or C;
- and X1 can be the same as or different from X2.
A ChoK inhibitor selected from the compounds set forth in Table 3.
A pharmaceutical composition comprising a compound selected from Table 1, or an isomer, tautomer, pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier.
A pharmaceutical composition comprising a compound selected from Table 2, or an isomer, tautomer, pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier.
A pharmaceutical composition comprising a compound selected from Table 3, or an isomer, tautomer, pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceuctially acceptable carrier.
A method of treating a subject suffering from a disorder or disease benefited by suppressing cellular apoptosis, the method comprising administering to the subject an amount of a choline kinase inhibitor effective to suppress cellular apoptosis.
A method for identifying a compound that directly modulates ChoK activity, the method comprising:
- a) obtaining a crystal structure of ChoK or obtaining information relating to a crystal structure of ChoK, and b) modeling a test compound into or on the crystal structure coordinates to determine whether the compound binds to ChoK, wherein modeling comprises determining the ability of the compound to bind to or associate with a choline (Cho) binding pocket of ChoK defined by structural coordinates of one or more ChoK amino acid residues forming the Cho binding pocket.
A method for identifying a compound that directly modulates ChoK activity, the method comprising using atomic coordinates of one or more of ChoK amino acid residues to generate a three-dimensional structure of a molecule comprising a Cho binding pocket of ChoK, and employing the three-dimensional structure to identify a compound that directly modulates the activity of ChoK.
Dependencies are inferred from the claim text.