US-12624031-B2 - Inhibitors of ubiquitin specific peptidase 22 (USP22) and uses thereof for treating diseases and disorders

Abstract

Disclosed are methods of treating diseases or disorders associated with the expression of Ubiquitin Specific Peptidase 22 (USP22). The disclosed methods may be utilized to treat diseases or disorders associated with cell proliferation, including cancer. Also disclosed are inhibitors of USP22 that specifically inhibit the EC:3.4.19.12 activity, or the thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal glycine of ubiquitin. The disclosed compounds may also be used in pharmaceutical compositions and methods for treatment of cell proliferative diseases or disorders associated with USP22 activity.

Inventors

• Deyu Fang
• Amy Tang
• Beixue Gao
• Elena Montauti
• Ming Yan
• Huiping Liu

Assignees

• NORTHWESTERN UNIVERSITY

Dates

Publication Date

20260512

Application Date

20230425

Claims (12)

1. 1 . A compound of formula or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from cyano and R 1 is —NH-phenyl, the phenyl substituted with halo, —CN, alkyl, alkoxy,—NO 2 , amino, or —COOH and wherein the alkyl is optionally substituted with a halo or amino, or halo or wherein R 2 is selected from alkyl and R 1 is —NH-phenyl, the phenyl optionally substituted with halo, —CN, alkyl, alkoxy, —NO 2 , amino, and —COOH and wherein the alkyl is optionally substituted with a halo or amino, or halo.
2. 2 . The compound of claim 1 having the formula or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R 3 are independently selected from hydrogen, halo, —CN, alkyl, alkoxy, —NO 2 , amino, and —COOH, wherein the alkyl is optionally substituted with a halo or amino, and wherein R 1 , R 2 , and R 3 are not each hydrogen.
3. 3 . The compound of claim 1 , wherein the compound is selected from
4. 4 . The compound of claim 1 , wherein the compound is
5. 5 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier, excipient, or diluent.
6. 6 . The pharmaceutical composition of claim 5 , wherein the composition comprises an effective amount of the compound for inhibiting biological activity of USP22 when administered to a subject in need thereof.
7. 7 . The pharmaceutical composition of claim 5 , wherein the composition comprises an effective amount of the compound for suppressing Treg cell activity in a subject in need thereof.
8. 8 . The pharmaceutical composition of claim 5 , wherein the composition comprises an effective amount of the compound for inhibiting ubiquitin specific peptidase activity (E.C. 3.4.19.12) of USP22 in a subject in need thereof.
9. 9 . A method of treating a subject in need of treatment for a disease or disorder associated with ubiquitin specific peptidase 22 (USP22) activity, the method comprising administering to the subject an effective amount of the pharmaceutical composition of claim 5 , wherein the disease or disorder is a cancer selected from the group consisting of lung cancer, gastric carcinoma, pancreatic cancer, melanoma, lymphoma, colon cancer, breast cancer, ovarian cancer, bladder cancer, prostate cancer, glioma, mesothelioma, neuroblastoma, mantle cell lymphoma, and acute myeloid leukemia.
10. 10 . The method of claim 9 , wherein the disease or disorder is lung cancer.
11. 11 . The method of claim 9 , wherein the disease or disorder is melanoma.
12. 12 . A method for inhibiting ubiquitin specific peptidase activity (E.C. 3.4.19.12) of USP22 in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of claim 5 .

Description

CROSS REFERENCE TO RELATED APPLICATIONS The present application claims priority to U.S. Provisional Patent Application No. 63/334,454 that was filed Apr. 25, 2022, the entire contents of which are hereby incorporated by reference. SEQUENCE LISTING A Sequence Listing accompanies this application and is submitted as an xml file of the sequence listing named “702581_02253.xml” which is 3,701 bytes in size and was created on Apr. 19, 2023. The sequence listing is electronically submitted via Patent Center and is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION The field of the invention relates to small molecule inhibitors of ubiquitin specific peptidase 22 (USP22) and the use thereof in treating diseases and disorders associated with USP22 biological activity. In particular, the field of the invention relates to small molecule inhibitors of the peptidase activity of USP22 which may be formulated as pharmaceutical compositions for treatment of immune deficiency, infectious diseases, and cell proliferative diseases and disorders such as cancer. The expression of ubiquitin specific peptidase 22 (USP22) is often increased in many, if not all types of human cancers. USP22 functions as a potential oncogene in tumorigenesis and progression in lung and colon cancer in part through diminishing the tumor suppressor p53 transcriptional activity and promoting cell cycle progression. Mice with genetic USP22 suppression in immune cells have better tumor rejection using multiple syngeneic tumor models including lung cancer, lymphoma, melanoma, and colon cancers. These results indicate that USP22 is an ideal therapeutic target in antitumor therapy because that, on one hand, inhibition of USP22 in tumor cells can directly induces their apoptosis and blocks cell cycle progression, on the other hand, USP22 suppression in immune cells enhances immunity. In addition, USP22 inhibition can improve immune response to combat all pathogens in treatment of infectious diseases and immune deficient diseases. SUMMARY OF THE INVENTION In an aspect of the current disclosure, compounds are provided. In some embodiments, the compounds have the formula or a pharmaceutically acceptable salt thereof, where R2 is selected from cyano and alkyl and R1 is —NH-phenyl, the phenyl optionally substituted with halo, —CN, alkyl, alkoxy, —NO2, amino, and —COOH and wherein the alkyl is optionally substituted with a halo or amino, or halo. In some embodiments, the compounds have the formula Ia. In some embodiments, the compounds have the formula Ib. In some embodiments, the compounds have the formula Ic. In some embodiments, R2 is selected from cyano and R1 is —NH-phenyl, the phenyl substituted with halo, —CN, alkyl, alkoxy, —NO2, amino, and —COOH and wherein the alkyl is optionally substituted with a halo or amino, or halo. In some embodiments, the compounds have the formula Ia. In some embodiments, the compounds have the formula Ib. In some embodiments, the compounds have the formula Ic. In some embodiments, R2 is selected from alkyl and R1 is —NH-phenyl, the phenyl optionally substituted with halo, —CN, alkyl, alkoxy, —NO2, amino, and —COOH and wherein the alkyl is optionally substituted with a halo or amino, or halo. In some embodiments, the compounds have the formula Ia. In some embodiments, the compounds have the formula Ib. In some embodiments, the compounds have the formula Ic. In some embodiments, the compounds have the formula or a pharmaceutically acceptable salt thereof, where R1, R2, and R3 are independently selected from hydrogen, halo, —CN, alkyl, alkoxy, —NO2, amino, and —COOH, wherein the alkyl is optionally substituted with a halo or amino, and wherein R1, R2, and R3 are not each hydrogen. In some embodiments, the compounds are selected from In some embodiments, the compound is In some embodiments, the compound is In some embodiments, the compound is selected from In another aspect of the current disclosure, pharmaceutical compositions are provided. In some embodiments, the pharmaceutical compositions comprise a compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the composition comprises an effective amount of the compound for inhibiting biological activity of USP22 when administered to a subject in need thereof. In some embodiments, the composition comprises an effective amount of the compound for suppressing Treg cell activity in a subject in need thereof. In some embodiments, the composition comprises an effective amount of the compound for inhibiting ubiquitin specific peptidase activity (E.C. 3.4.19.12) of USP22 in a subject in need thereof. In another aspect of the current disclosure, methods of treating a subject in need of treatment for a disease or disorder associated with ubiquitin specific peptidase 22 (USP22) activity are provided. In some embodiments, the methods comprise administering to the subject an effec