A Method of Treating Cancer
The present invention relates to a method of treating cellular proliferative diseases, in particular cancer, which comprises administering a modulator of the activity of the mitotic kinesin KSP, wherein the activity of the KSP modulator is dependent on the presence of microtubules. It is believed that the KSP modulators utilized in the instant method bind to the KSP protein in a previously unreported manner, since the compounds do not bind competitively with respect to either microtubules or ATP, the substrates of KSP. The modulators useful in the instant methods are furthermore not active against the non-microtubule stimulated activity of KSP. Cellular proliferative diseases that may be treated using the method disclosed herein are, for example cancer, hyperplasias, restenosis, cardiac hypertrophy, immune disorders and inflammation.
1 . A method of identifying a compound that specifically modulates the activity of a kinesin motor protein bound to a microtubule, said kinesin motor protein having a microtubule binding site and a kinesin ATPase binding site, said method comprising the steps of:
a) assaying for competitive inhibition of said motor protein by said compound at said kinesin ATPase binding site;
b) assaying for competitive inhibition of said motor protein by said compound at said microtubule binding site;
c) assaying for inhibition of said motor protein by said compound in the absence of microtubules;
d) assaying for inhibition of said motor protein by said compound in the presence of microtubules;
e) identifying a compound as a kinesin-bound-to-microtubule modulator when said compound inhibits said motor protein activity in the presence of microtubules, is not a competitive modulator at said microtubule binding site and at said kinesin ATPase binding site, and does not inhibit said motor protein activity when microtubules are absent.
2 . The method according to claim 1 wherein the compound is a polypeptide.
3 . The method according to claim 1 wherein the compound is a small organic molecule.
4 . The method according to claim 3 wherein the small organic molecule is a part of a combinatorial library when contacted with the kinesin motor protein.
5 . The method according to claim 1 wherein the kinesin motor protein is KSP.
6 . A method of modulating kinesin motor activity, said method comprising contacting a kinesin motor, said kinesin motor protein having a microtubule binding site and a kinesin ATPase binding site, with a small organic molecule that inhibits said motor protein activity in the presence of microtubules, is not a competitive modulator at said microtubule binding site and at said kinesin ATPase binding site, and does not inhibit said motor protein activity when microtubules are absent.
7 . The method according to claim 6 wherein the kinesin motor protein is KSP.
8 . A method of modulating cellular growth in an organism, said method comprising administering to said organism a composition comprising a pharmaceutically acceptable carrier and a compound in a quantity sufficient to alter said cellular growth in an organism, said compound identified by the method according to claim 1 .
9 . The method of claim 8 , wherein said organism is an animal.
10 . The use of the compound identified by the method according to claim 1 for the preparation of a medicament useful for the treatment or prevention of cancer.
11 . The use of the compound selected from:
or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful for the treatment or prevention of cancer.
12 . A compound selected from:
or a pharmaceutically acceptable salt thereof.