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US 12,329,755 B2Granted
Bromodomain inhibitors to target therapy-resistant cancer
AssigneeUniversity of Tennessee Research Foundation
InventorsDuane Miller, Lawrence M. Pfeffer, Yali He, Debolina Ganguly
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Abstract
Novel inhibitors of the bromodomain of Brahma-related gene 1 (BRG1) are described. Also described are methods of treating glioblastoma using inhibitors of the BRG1 bromodomain in combination with chemotherapeutics, such as DNA alkylating agents. As described herein, the inhibitors sensitize glioblastoma cells, including chemoresistant glioblastoma cells, to DNA alkylating agents, for example, temozolomide and carmustine.
Claims28
A compound having the structure of Formula (I):
- wherein:
- represents a single or double bond;
- Ar is selected from cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
- R is H, halo, amino, thiol, or hydroxy;
- and Y is H or halo;
- or
- where R and Y together from a group selected from —N═CH—NH—, —N═N—NH—, and —CH═N—NH—;
- R1 and R2 are each independently selected from the group consisting of H, cyano, halo, alkyl, substituted alkyl, perhaloalkyl, alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl;
- R3, R4 and R5 are each H;
- and
- X is O, S, or NH;
- or
- wherein (i) X and R5 together comprise —N—NH— and/or wherein R3 and R4 together form an alkylene group, optionally ethylene or (ii) R3 and R5 together form a covalent bond or methylene group;
- or a pharmaceutically acceptable salt thereof, subject to the proviso that the compound is not PFI-3.
11 more elements
A method of treating glioblastoma in a subject in need thereof, the method comprising:
- (a) administering to the subject a compound of Formula (I)
- wherein:
- represents a single or double bond;
- Ar is selected from cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
- R is H, halo, amino, thiol, or hydroxy and Y is H or halo;
- or
- wherein R and Y together form a group selected from —N═CH—NH—, —N═N—NH—, and —CH═N—NH—;
- R1 and R2 are each independently selected from the group consisting of H, cyano, halo, alkyl, substituted alkyl, perhaloalkyl, alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl;
- R3, R4 and R5 are each H;
- and
- X is O, S, or NH;
- or
- wherein (i) X and R5 together comprise —N—NH— and/or R3 and R4 together form an alkylene group, optionally ethylene or (ii) R3 and R5 together form a covalent bond or methylene group;
- or a pharmaceutically acceptable salt thereof, and optionally wherein the compound of Formula (I) is not PFI-3;
- and
- (b) administering to the subject a chemotherapeutic compound, wherein said chemotherapeutic compound is a DNA alkylating agent.
13 more elements
Dependencies are inferred from the claim text.