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US 2004/0002145 A1Published application
Crystal structure of liganded cFMS kinase domain
OwnerLisa Marie Shewchuk, Anne Moore Hassell +6inventors
InventorsLisa Marie Shewchuk, Anne Moore Hassell, William David Holmes, James Marvin Veal, Holly Kathleen Emmerson, David Lee Musso, Stanley Dawes Chamberlain, Gregory Edward Peckham
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Abstract
A crystal structure of the cfms kinase domain, co-crystal structure with a bound small molecule, as well as methods of using the same in the discovery of cfms inhibitors and in the treatment of diseases mediated by inappropriate cfms activity.
Claims14
A cFMS kinase domain in liganded crystalline form, comprising the amino acid sequence of SEQ ID NO:
- 1 or 2 and having the structural coordinates of Table 2.
A method of cFMS inhibitor design, comprising:
- generating a three dimensional computer model which represents a cFMS kinase domain in liganded form, said kinase domain described by the amino acid sequence of SEQ ID NO:
- 1 or 2 and having the structural coordinates of Table 2;
- evaluating compounds as potential cFMS inhibitors using said model;
- and
- selecting compounds for further testing based on said evaluation.
2 more elements
A method of cfms inhibitor design, comprising:
- generating a three dimensional computer model which represents a cfms kinase domain in liganded form, said kinase domain described by the amino acid sequence of SEQ ID NO:
- 1 or 2 and having the structural coordinates of Table 2;
- evaluating compounds as potential cFMS inhibitors using said model;
- wherein said evaluation comprises identifying compounds capable of at least one of the following cFMS kinase domain/compound interactions:
- (i) one or more interactions with amino acid residues of the cFMS kinase domain hinge region;
- (ii) one or more interactions with amino acid residues of the cFMS kinase domain adenine pocket,
- (iii) one or more interactions with amino acid residues of the cFMS kinase sugar pocket and phosphate region,
- (iv) one or more interactions with amino acid residues of the cFMS kinase domain back pocket, and
- (v) one or more interactions with amino acid residues of the cFMS kinase domain solvent interface;
- and
- selecting compounds for further testing based on said evaluation.
8 more elements
A method of cfms inhibitor design, comprising:
- generating a three dimensional computer model which represents a cfms kinase domain in liganded form, said kinase domain described by the amino acid sequence of SEQ ID NO:
- 1 or 2 and having the structural coordinates of Table 2;
- evaluating compounds as potential cFMS inhibitors using said model;
- wherein said evaluation comprises identifying compounds capable of at least one of the following cFMS kinase domain/compound interactions:
- (i) one or more interactions with amino acid residues 663, 664, 665, 666, 667, 668, and 669;
- (ii) one or more interactions with amino acid residues 588, 614, 647, and 785,
- (iii) one or more interactions with amino acid residues 596 and 797 and/or one or more hydrogen bonding interactions with amino acid residue residue 796,
- (iv) one or more interactions with amino acid residues 550, 640, 646, 769, and 776, and
- (v) one or more interactions with residues 668 and 672;
- and
- selecting compounds for further testing based on said evaluation.
8 more elements
A method of treating a disorder characterized by inappropriate cfms activity in a mammal, comprising:
- administering to said mammal a therapeutically effective amount of a compound that can form a complex with a cfms kinase domain thereby resulting in a cfms kinase domain in liganded form, said kinase domain in liganded form being described by the amino acid sequence of SEQ ID NO:
- 1 or 2 and the structural coordinates of Table 2, wherein said complex is characterized by at least one of the following cfms kinase domain/compound interactions:
- (i) one or more interactions with amino acid residues of the cFMS kinase domain hinge region;
- (ii) one or more interactions with amino acid residues of the cFMS kinase domain adenine pocket,
- (iii) one or more interactions with amino acid residues of the cFMS kinase sugar pocket and phosphate region,
- (iv) one or more interactions with amino acid residues of the cFMS kinase domain back pocket, and
- (v) one or more interactions with amino acid residues of the cFMS kinase domain solvent interface.
4 more elements
A method of inhibiting cfms in a mammal, comprising:
- administering to said mammal a therapeutically effective amount of a compound that can form a complex with a cfms kinase domain thereby resulting in a cfms kinase domain in liganded form, said kinase domain in liganded form being described by the amino acid sequence of SEQ ID NO:
- 1 or 2 and the structural coordinates of Table 2, wherein said complex is characterized by at least one of the following cfms kinase domain/compound interactions:
- (i) one or more interactions with amino acid residues of the cFMS kinase domain hinge region;
- (ii) one or more interactions with amino acid residues of the cFMS kinase domain adenine pocket,
- (iii) one or more interactions with amino acid residues of the cFMS kinase sugar pocket and phosphate region,
- (iv) one or more interactions with amino acid residues of the cFMS kinase domain back pocket, and
- (v) one or more interactions with amino acid residues of the cFMS kinase domain solvent interface.
4 more elements
A cFMS kinase domain/inhibitor complex which includes a cFMS liganded kinase domain described by the amino acid sequence of SEQ ID NO:
- 1 or 2 and the structural coordinates of Table 2 and a compound capable of at least one of the following interactions with the cFMS kinase domain:
- (i) one or more interactions with amino acid residues of the cFMS kinase domain hinge region;
- (ii) one or more interactions with amino acid residues of the cFMS kinase domain adenine pocket,
- (iii) one or more interactions with amino acid residues of the cFMS kinase sugar pocket and phosphate region,
- (iv) one or more interactions with amino acid residues of the cFMS kinase domain back pocket, and
- (vii) one or more interactions with amino acid residues of the cFMS kinase domain solvent interface.
3 more elements
A compound of formula (I):
- 64
- or a salt, solvate, or physiologically functional derivative thereof:
- wherein
- R1 is —H or C1-C6 alkyl;
- R2 is —H, C1-C6 alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl, heteroaryl, or —(CH2)pR6;
- n is 1 or 2;
- p is 1, 2, or 3;
- R3 is —H or C1-C6 alkoxy;
- R4 is C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkoxy, -halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, aryl, —SR5, or n is 2 and each R4 together with the phenyl ring to which they are attached form the group
- 65
- R5 is C1-C6 alkyl;
- and
- R6 is NR5R5, heterocyclyl, aryl, or heteroaryl.
10 more elements
Dependencies are inferred from the claim text.