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|Title:||Inhibitors of Bruton's tyrosine kinase|
|Abstract:||Described herein are irreversible kinase inhibitor compounds, methods for synthesizing such irreversible inhibitors, and methods for using such irreversible inhibitors in the treatment of diseases. Further described herein are methods, assays and systems for determining an appropriate irreversible inhibitor of a protein, including a kinase.|
|Inventor(s):||Honigberg; Lee (San Francisco, CA), Verner; Erik (Belmont, CA), Buggy; Joseph J. (Mountain View, CA), Loury; David (San Jose, CA), Chen; Wei (Fremont, CA)|
|Assignee:||Pharmacyclics, Inc. (Sunnyvale, CA)|
|Filing Date:||Mar 27, 2008|
|Claims:||1. A method of identifying an irreversible inhibitor of a Bruton's tyrosine kinase (Btk) comprising: (1) contacting Btk with a compound of Formula VII; (2) contacting at least one non-kinase molecule having at least one accessible SH group including glutathione and/or hemoglobin with the compound of Formula VII; and (3) determining the covalent binding of the compound of Formula VII with Btk and the at least one non-kinase molecule; and repeating steps (1), (2), and (3) for at least one other compound of Formula VII, wherein the compound of Formula (VII) has the structure: ##STR00125## wherein: ##STR00126## is a moiety that binds to the active site of a Btk kinase; Y is an optionally substituted group selected from among alkylene, heteroalkylene, arylene, heteroarylene, heterocycloalkylene, cycloalkylene, alkylenearylene, alkyleneheteroarylene, alkylenecycloalkylene, and alkyleneheterocycloalkylene; Z is C(.dbd.O), OC(.dbd.O), NHC(.dbd.O), NCH.sub.3C(.dbd.O), C(.dbd.S), S(.dbd.O).sub.x, OS(.dbd.O).sub.x, NHS(.dbd.O).sub.x, where x is 1 or 2; R.sub.7 and R.sub.8 are independently selected from among H, unsubstituted C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4alkyl, unsubstituted C.sub.1-C.sub.4heteroalkyl, substituted C.sub.1-C.sub.4heteroalkyl, unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted C.sub.3-C.sub.6cycloalkyl, unsubstituted C.sub.2-C.sub.6heterocycloalkyl, and substituted C.sub.2-C.sub.6heterocycloalkyl; or R.sub.7 and R.sub.8 taken together form a bond; and R.sub.6 is H, substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or unsubstituted C.sub.1-C.sub.4heteroalkyl, C.sub.1-C.sub.6alkoxyalkyl, C.sub.1-C.sub.8alkylaminoalkyl, C.sub.1-C.sub.8hydroxyalkylaminoalkyl, C.sub.1-C.sub.8alkoxyalkylaminoalkyl, substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C.sub.2-C.sub.8heterocycloalkyl, substituted or unsubstituted heteroaryl, C.sub.1-C.sub.4alkyl(aryl), C.sub.1-C.sub.4alkyl(heteroaryl), C.sub.1-C.sub.4alkyl(C.sub.3-C.sub.8cycloalkyl), or C.sub.1-C.sub.4alkyl(C.sub.2-C.sub.8heterocycloalkyl); wherein a desired irreversible inhibitor is selective for Btk relative to glutathione and hemoglobin. |
2. The method of claim 1, further comprising (4) comparing the covalent binding of the compound of Formula VII with Btk and the at least one non-kinase molecule; and repeating steps (1), (2), (3) and (4) for at least one other compound of Formula VII.
3. The method of claim 2, wherein the structure of ##STR00127## of each compound is not varied.
4. The method of claim 1, further comprising contacting each kinase with an Activity Probe.
5. The method of claim 1, wherein steps (1) and (2) are conducted in vivo and step (3) is conducted in part using an Activity Probe.
6. The method of claim 1, wherein the determining step uses mass spectrometry.
7. The method of claim 1, wherein the determining step uses fluorescence.
8. The method of claim 2, further comprising analyzing the structure-function activity relationship between the structure of Y--Z and/or ##STR00128## of each compound, and the binding and/or selectivity of each compound to Btk.