US 2021/0008043 A1 · Substituted Chromenones, IRE1 Inhibitors, and Methods of Using Same

Abstract

The present invention includes substituted chromenones that are useful to inhibit the IRE1/XBP-1 pathway. In certain embodiments, the compounds of the invention inhibit IRE1's RNase activity. In other embodiments, the compounds of the invention are useful to treat or prevent a cancer that involve activation of the ER stress response. The invention also relates, in certain aspects, to the discovery that secretory IgM (sIgM) can orchestrate an immunosuppressive microenvironment by recruiting myeloid-derived suppressor cells (MDSCs) into different tumor models, such as but not limited to solid tumors (such as but not limited to lung cancer) and tumors that have high levels of secreted IgM. In certain embodiments, sIgM produced by B cells or CLL cells can contribute to the accumulation of MDSCs in a tumor. In other embodiments, inhibition of the IRE1/XBP-1 pathway can ablate, minimize, or reduce MDSC levels in a tumor.

Claims39

Dependent claims

A compound of formula (I), or a salt or solvate thereof:

wherein:
R1 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, HC(═O)—, (C1-C6 alkyl)-C(═O)—, (C2-C6 alkenyl)-C(═O)—, (C2-C6 alkynyl)-C(═O)—, (C3-C8 cycloalkyl)-C(═O)—, (C1-C6 alkyl)-OC(═O)—, (C2-C6 alkenyl)-OC(═O)—, (C2-C6 alkynyl)-OC(═O)—, and (C3-C8 cycloalkyl)-OC(═O)—, wherein the alkyl, alkenyl, alkynyl, or cycloalkyl are independently optionally substituted;
R2 is selected from the group consisting of optionally substituted 1,3-dioxolan-2-yl, optionally substituted 1,3-dioxan-2-yl, —CH═N—OR5, and —CH═N—NR5R6, wherein:
R5 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, HC(═O)—, (C1-C6 alkyl)-C(═O)—, (C2-C6 alkenyl)-C(═O)—, (C2-C6 alkynyl)-C(═O)—, and (C3-C8 cycloalkyl)-C(═O)—, wherein the alkyl, alkenyl, alkynyl, or cycloalkyl are independently optionally substituted, and
R6 is selected from the group consisting of H and C1-C6 alkyl, wherein the alkyl is optionally substituted,
or R5 and R6 combine with the N atom to which they are bound to form an optionally substituted heterocyclyl or heteroaryl;
R3 is a group that can be deprotected in vitro or in vivo to —OH;
and
R4 is selected from the group consisting of H, —OH, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C3-C8 cycloalkoxy, HC(═O)O—, (C1-C6 alkyl)-C(═O)O—, (C2-C6 alkenyl)-C(═O)O—, (C2-C6 alkynyl)-C(═O)O—, and (C3-C8 cycloalkyl)-C(═O)O—, wherein the alkyl, alkenyl, alkynyl, or cycloalkyl are independently optionally substituted.

6 more elements

A method of:

(A) reducing or minimizing levels and/or production of sIgM in a subject suffering from cancer,
(b) minimizing or reducing number or activity of myeloid-derived suppressor cells (MDSCs) in a subject suffering from cancer,
(c) stimulating or increasing proliferation of anti-tumor T cells in a subject suffering from a sIgM-assisted or sIgM-driven cancer, or
(d) treating or preventing a sIgM-assisted or sIgM-driven cancer in a subject, if levels of sIgM in a biological sample from the subject are higher than in a control biological sample,
wherein the method comprises administering to the subject a therapeutically effective amount of a IRE1 RNAse inhibitor.

2 more elements

Dependencies are inferred from the claim text.

Substituted Chromenones, IRE1 Inhibitors, and Methods of Using Same

Life of this patent

Substituted Chromenones, IRE1 Inhibitors, and Methods of Using Same

Life of this patent

Abstract

Claims39