Use of acetylated tubulin as a biomarker of drug response to furazanobenzimidazoles

A method of determining whether a subject is resistant to treating a disease by administration to said subject a compound of formula I

• wherein
• R represents phenyl, thienyl or pyridinyl
• wherein phenyl is optionally substituted by one or two substituents independently selected from alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, phenyl, hydroxy, lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, phenyl-lower alkoxy, lower alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, lower alkoxycarbonylamino, lower alkylcarbonylamino, substituted amino wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl, lower alkylcarbonyl, carboxy, lower alkoxycarbonyl, cyano, halogen, and nitro;
• and
• wherein two adjacent substituents are methylenedioxy;
• and wherein pyridinyl is optionally substituted by lower alkoxy, amino or halogen;
• wherein Y is oxygen or nitrogen substituted by hydroxy or lower alkoxy;
• or when R1 is phenyl or pyridinyl, X is additionally oxygen,
• R1 represents hydrogen, lower alkylcarbonyl, hydroxy-lower alkyl or cyano-lower alkyl;
• R2, R3 and R6 represent hydrogen;
• R4 and R5, independently of each other, represent hydrogen, lower alkyl or lower alkoxy;
• or R4 and R5 together represent methylenedioxy;
• wherein said prefix denotes a radical having up to 7 carbon atoms;
• or pharmaceutically acceptable derivatives thereof;
• said method comprising;
• a) obtaining a sample from said subject;
• b) measuring the level of the acetylated tubulin proteins in said sample;
• and
• c) thereby determining from said measured level of the acetylated tubulin proteins
• whether the subject is resistant to treating of said disease with said compound of formula I.

A method for predicting the response to treatment of a disease in a patient subject by administration of a compound of general formula I

• wherein
• R represents phenyl, thienyl or pyridinyl
• wherein phenyl is optionally substituted by one or two substituents independently selected from alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, phenyl, hydroxy, lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, phenyl-lower alkoxy, lower alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, lower alkoxycarbonylamino, lower alkylcarbonylamino, substituted amino wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl, lower alkylcarbonyl, carboxy, lower alkoxycarbonyl, cyano, halogen, and nitro;
• and wherein two adjacent substituents are methylenedioxy;
• and wherein pyridinyl is optionally substituted by lower alkoxy, amino or halogen;
• wherein Y is oxygen or nitrogen substituted by hydroxy or lower alkoxy;
• or when R1 is phenyl or pyridinyl, X is additionally oxygen,
• R1 represents hydrogen, lower alkylcarbonyl, hydroxy-lower alkyl or cyano-lower alkyl;
• R2, R3 and R6 represent hydrogen;
• R4 and R5, independently of each other, represent hydrogen, lower alkyl or lower alkoxy;
• or R4 and R5 together represent methylenedioxy;
• or pharmaceutically acceptable derivatives thereof,
• and wherein said prefix lower denotes a radical having up to 7 carbon atoms,
• said method comprising the steps of:
• a) measuring the level of the acetylated tubulin, proteins in a sample obtained from a patient to obtain a value or values representing this level;
• and
• b) comparing the value or values of the levels from step a) with a standard value or a set of standard values which comparison is predictive of responsiveness to compounds of formula I.

The method of treating a neoplastic or autoimmune disease in a patient in need thereof, said method comprising

• a) obtaining a sample of biologic material from the body of said patient;
• b) determining the level of the acetylated tubulin proteins in said sample;
• and
• c) then treating the patient with a compound of formula I as described above or a pharmaceutically acceptable derivative thereof, if the level of acetylated tubulin proteins in said sample is not higher than a standard value or set of standard values for the level of acetylated tubulin proteins.