Novel Kinase Inhibition Models and Their Uses
AssigneeArQule, Inc.
InventorsMark A. Ashwell, Rocio Palma, Sudharshan Eathiraj
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Abstract
The present invention provides a c-Met inhibition model. The invention further provides a method to derive inhibition models for other kinases. The kinase inhibition models of the present invention can be used to design or screen for inhibitors for kinases.
Claims20
A method for generating a kinase inhibition model, comprising:
- a) performing sequence alignment between the amino acid sequences of the kinase and the c-Met kinase domain of SEQ ID NO:
- 2;
- b) identifying non-conserved amino acids between the kinase and the c-Met kinase domain;
- c) replacing in the crystal structure of the c-Met kinase domain the amino acids corresponding to the non-conserved amino acids with the amino acids of the kinase corresponding to the non-conserved amino acids;
- and
- d) refining the crystal structure with the amino acids of the kinase corresponding to the non-conserved amino acids.
A c-Abl inhibition model comprising the crystallography coordinates of c-Abl amino acids L—266, G—267, Y—271, V—274, A—287, V—288, K—289, V—317, I—331, T—333, E—334, F—335, M—336, T—337, Y—338, G—339, N—340, L—388, A—398, D—399, F—400, S—403, and R—404 which are within about a root mean square deviation of not more than about 1.5 Å from the backbone atoms of said amino acids according to Table 5.
An FGFR-2 inhibition model comprising the crystallography coordinates of FGFR-2 amino acids L—487, G—488, F—492, V—495, A—515, V—516, K—517, I—548, V 562, V 564, E—565, Y 566, A 567, S 568, K 569, G—570, N—571, L—633, A—643, D—644, F—645, A 648, and R—649 which are within about a root mean square deviation of not more than about 1.5 Å from the backbone atoms of said amino acids according to Table 7.
Dependencies are inferred from the claim text.