INHIBITORS OF THE IRE-1/XBP-1 PATHWAY AND METHODS OF USING THEREOF

摘要

Disclosed are XBP-1/IRE-1 inhibitors having formula disclosed herein. Methods of making and using these inhibitors for the treatment of cancer, in particular B cell cancers, are also disclosed. Also disclosed is a genetic XBP-1-knockout cancer mouse model. In still further aspects, the disclosed subject matter relates to methods for treating oncological and inflammatory disorders in a patient. For example, disclosed herein are methods whereby an effective amount of a compound or composition disclosed herein is administered to a patient having an oncological disorder, for example B-cell chronic lymphocytic leukemia (CLL), and who is in need of treatment thereof. XBP-1 deficiency causes leukemic cells to acquire phenotypes that are disadvantageous for their survival, such as compromised BCR signaling capability and increased surface expression of S1 P1.

主权项

1. A compound having Formula I: wherein the dotted lines between Y and C1 and between C1 and X represent single or double bonds; A is a chalcogen containing moiety; D is chosen from hydrogen, hydroxyl, carbonyl, alkoxy, halogen, thiol, thioalkyl, aryl, alkylaryl, or alkyl; R3 and R4 are independently chosen from hydrogen, halogen, hydroxy, amino, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkylaryl, aryl, alkylheteroaryl, or heteroaryl, any of which is optionally substituted with carbonyl, alkyl, amino, amido, —NR6R7, —C(O)NR6R7, alkoxy, alkylhydroxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl, halo, hydroxy, thiol, cyano, or nitro; Y is chosen from S, N, O, or C, wherein when Y is C, the dotted line between Y and C1 in the ring represents a double bond and the dotted line between C1 and X is a single bond; and wherein when Y is S, N, or O, the dotted line between Y and C1 in the ring represents a single bond and the dotted line between C1 and X represents a double bond; X is hydrogen, oxygen, halogen, hydroxy, amino, thiol, thioalkyl, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkylaryl, aryl, alkylheteroaryl, or heteroaryl, any of which is optionally substituted with acetyl, alkyl, amino, amido, —NR6R7, —C(O)NR6R7, alkoxy, alkylhydroxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl, halo, hydroxy, thiol, cyano, or nitro; R1 and R2 are independently chosen from hydrogen, benzoate, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkylaryl, aryl, alkylheteroaryl, or heteroaryl, any of which is optionally substituted with acetyl, alkyl, amino, amido, —NR6R7, —C(O)NR6R7, alkoxy, alkylhydroxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl, halo, hydroxy, thiol, cyano, or nitro; or R1 and R2 together with the atoms to which they are attached form a 5-7 membered cyclic moiety wherein any of the additional atoms are optionally heteroatoms and the 5 to 7-membered ring is, optionally, a heterocyclic structure that is optionally substituted; and R6 and R7 are independently H, alkyl; or R6 and R7 together with the atoms to which they are attached form a 3-7 membered cyclic moiety wherein any of the additional atoms are optionally heteroatoms and the 3 to 7-membered ring is, optionally, a heterocyclic structure that is optionally substituted; or a pharmaceutically acceptable salt thereof.