Methods of identifying hsp90 inhibitors with less ocular toxicity

Abstract

Provided is a method of identifying Hsp90 inhibitors with substantially less ocular toxicity or with substantially improved ocular toxicity profile. The method comprises measuring the respective concentrations of an Hsp90 inhibitor in the retina and plasma at certain time points following the administration of the Hsp90 inhibitor in a subject, and determining the concentration ratio of the Hsp90 inhibitor between retina and plasma, where a certain ratio is indicative that the Hsp90 inhibitor has substantially less ocular toxicity. The method also includes identifying an Hsp90 inhibitor with substantially less ocular toxicity, or with a substantially improved ocular toxicity profile, by determining the elimination rate of the Hsp90 inhibitor from the retina following administration of the Hsp90 inhibitor, where a certain elimination rate is indicative that the Hsp90 inhibitor will induce substantially less ocular toxicity.

1 . A method of predicting whether an Hsp90 inhibitor will induce ocular toxicity in vivo, comprising determining the concentration ratio of an Hsp90 inhibitor between retina and plasma following administration of the Hsp90 inhibitor to a subject, where a certain concentration ratio is indicative that administration of the Hsp90 inhibitor will induce ocular toxicity in vivo. 
     
     
         2 . The method of  claim 1 , wherein a concentration ratio of above 25 as determined at about 6 hours following the administration of the Hsp90 inhibitor is an indication that the Hsp90 inhibitor will induce toxicity in vivo. 
     
     
         3 . The method of  claim 1 , wherein the subject is an animal. 
     
     
         4 . The method of  claim 3 , wherein the animal is a rat. 
     
     
         5 - 6 . (canceled) 
     
     
         7 . A method of identifying an Hsp90 inhibitor with substantially less ocular toxicity, comprising administering to a subject an effective amount of an Hsp90 inhibitor or a pharmaceutically acceptable salt or carrier thereof, and determining the concentration ratio of the Hsp90 inhibitor between retina and plasma, wherein a certain concentration ratio is indicative that administration of the Hsp90 inhibitor will cause substantially less ocular toxicity. 
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 7 , wherein the subject is an animal. 
     
     
         10 . The method of  claim 9 , wherein the animal is a rat. 
     
     
         11 . A method of predicting an ocular toxicological effect of an Hsp90 inhibitor, comprising administering to a subject an effective amount of an Hsp90 inhibitor or a pharmaceutically acceptable salt or carrier thereof, and determining the concentration ratio of the Hsp90 inhibitor between retina and plasma, wherein a certain concentration ratio is indicative that administration of the Hsp90 inhibitor will have an ocular toxicological effect. 
     
     
         12 . (canceled) 
     
     
         13 . A method of identifying an Hsp90 inhibitor with substantially less ocular toxicity, comprising the steps of:
 a) administering to a subject an effective amount of an Hsp90 inhibitor or a pharmaceutically acceptable salt or carrier thereof;   b) measuring the respective concentrations of the Hsp90 inhibitor in the retina and plasma;   c) determining the concentration ratio of the Hsp90 inhibitor between retina and plasma, wherein a certain ratio is indicative that the Hsp90 inhibitor will have substantially less ocular toxicity; and   d) optionally, further evaluating the Hsp90 inhibitor for its therapeutic use.   
     
     
         14 . The method of  claim 13 , wherein a concentration ratio in step c) of about 25% or below when step b) is performed at about 6 hours following the administration of the Hsp90 inhibitor in an indication that the Hsp90 inhibitor will have substantially less ocular toxicity, and the method further comprising evaluating the Hsp90 inhibitor for its anticancer utility. 
     
     
         15 . The method of  claims 13 , wherein the subject is an animal, 
     
     
         16 . The method of  claim 15 , wherein the animal is a rat. 
     
     
         17 - 20 . (canceled)