Compounds and methods useful for treating or preventing hematological cancers

Abstract

The present invention includes methods of treating patients with acute myeloid leukemia across a range of genetic subtypes with DHODH inhibitors, such as 6-fluoro-2-(2′-fluoro-[1,1′-biphenyl]-4-yl)-3-methylquinoline-4-carboxylic acid).

1 - 11 . (canceled) 
     
     
         12 . A method of treating a hematological cancer in a subject in need thereof comprising:
 (a) administering to the subject a first dose of a dihydroorotate dehydrogenase (DHODH) inhibitor;   (b) detecting dihydroorotate (DHO) and/or uridine in a biological sample obtained from the subject; and   (c) administering a second dose of a DHODH inhibitor, wherein the amount and or timing of the administration is modified based on the amounts of DHO and/or uridine detected, thereby treating the hematological malignancy in the subject.   
     
     
         13 . The method according to  claim 12  wherein the amount and/or timing of DHODH inhibitor administration is sufficient to increase levels of dihydroorotate by at least about 100-500 fold. 
     
     
         14 . The method according to  claim 12 , wherein the second dose of DHODH inhibitor is administered after the amount of DHO has returned to baseline. 
     
     
         15 . The method according to  claim 12 , wherein the method comprises:
 (a) administering to the subject a first dose of 6-fluoro-2-(2′-fluoro-[1,1′-biphenyl]-4-yl)-3-methylquinoline-4-carboxylic acid, or a salt or solvate thereof;   (b) detecting DHO and/or uridine in a biological sample obtained from the subject; and   (c) administering a second dose of 6-fluoro-2-(2′-fluoro-[1,1′-biphenyl]-4-yl)-3-methylquinoline-4-carboxylic acid), or a salt or solvate thereof, wherein the amount and/or timing of the administration is modified based on the amounts of DHO and/or uridine detected, thereby treating the hematological cancer in the subject.   
     
     
         16 . The method according to  claim 15 , wherein the second dose of DHODH inhibitor is administered after the amount of DHO has returned to baseline. 
     
     
         17 . The method according to  claim 12 , wherein the second dose is administered when the amount of uridine is 10-25% greater than the level of uridine present 12 hours after administration of the first dose.