Nuclear transport modulators and uses thereof
Inventors
Baloglu, Erkan • Shacham, Sharon • McCauley, Dilara • Kashyap, Trinayan • Senapedis, William • Landesman, Yosef • Golan, Gali • Kalid, Ori • Shechter, Sharon
Assignees
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Publication Number
US-11124493-B2
Publication Date
2021-09-21
Expiration Date
Abstract
The present invention relates to compounds of formula I: and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds of formula I or their pharmaceutically acceptable salts, and methods of using said compounds, salts and compositions in the treatment of various disorders associated with CRM1 activity.
Core Innovation
The disclosure provides substituted 1,2,4-triazole nuclear-transport modulators, including 3,5-bis(trifluoromethyl)phenyl-1,2,4-triazole derivatives with acrylate, acrylic acid, or acrylamide functionalities, and pharmaceutically acceptable salts thereof that function as CRM1/exportin-1 inhibitors. The compounds act to retain regulatory proteins in the nucleus and inhibit nuclear export in cellular assays. Compound 124 demonstrates CRM1/XPO1 inhibition dependent on Cys528 that persists after washout, induces dose-dependent XPO1 degradation, and enhances nuclear localization of XPO1 cargoes.
Methods comprise administering a therapeutically effective amount of a structurally represented triazole compound or a pharmaceutically acceptable salt thereof to treat specified cancers, myelodysplastic syndrome, and inflammatory disorders. Therapeutic indications include multiple myeloma, diffuse large B-cell lymphoma, acute myeloid leukemia, follicular lymphoma, colorectal cancer, prostate cancer, nasopharyngeal cancer, and inflammatory bowel disease. The disclosure also describes combining the compounds with radiation for cancer treatment, including non-small cell lung cancer, alongside preclinical inhibition of cancer-cell growth, xenograft tumors, arthritis clinical scores, and glioblastoma spheroids.
Claims Coverage
The claims identify six independent claims directed to methods of treating specified cancers or disorders by administering a therapeutically effective amount of a structurally represented compound or a pharmaceutically acceptable salt thereof.
Treatment of specified hematologic cancers
Administering to a subject in need thereof a therapeutically effective amount of the structurally represented compound or a pharmaceutically acceptable salt thereof to treat multiple myeloma, diffuse large B-cell lymphoma, acute myeloid leukemia, or follicular lymphoma, with dependent claims specifying multiple myeloma, diffuse large B-cell lymphoma, or oral administration.
Treatment of colorectal cancer
Administering to a subject in need thereof a therapeutically effective amount of the structurally represented compound or a pharmaceutically acceptable salt thereof to treat colorectal cancer.
Treatment of prostate cancer
Administering to a subject in need thereof a therapeutically effective amount of the structurally represented compound or a pharmaceutically acceptable salt thereof to treat prostate cancer.
Treatment of myelodysplastic syndrome
Administering to a subject in need thereof a therapeutically effective amount of the structurally represented compound or a pharmaceutically acceptable salt thereof to treat myelodysplastic syndrome.
Treatment of inflammatory bowel disease
Administering to a subject in need thereof a therapeutically effective amount of the structurally represented compound or a pharmaceutically acceptable salt thereof to treat inflammatory bowel disease, with a dependent claim specifying Crohn's disease or ulcerative colitis.
Treatment of nasopharyngeal cancer
Administering to a subject in need thereof a therapeutically effective amount of the structurally represented compound or a pharmaceutically acceptable salt thereof to treat nasopharyngeal cancer.
The independent claims cover treatment methods using the recited compound or its pharmaceutically acceptable salt across six disease indications, including specified hematologic cancers, colorectal cancer, prostate cancer, myelodysplastic syndrome, inflammatory bowel disease, and nasopharyngeal cancer, with dependent claims specifying cancer subtypes, oral administration, and inflammatory bowel disease subtypes.
Stated Advantages
Compound 124 shows broad cancer-cell growth inhibition and reduces tumor growth in the reported xenograft models.
Compound 124 reduces arthritis incidence and clinical scores in the reported mouse arthritis model.
Compound 124 inhibits growth of U87MG and U251MG glioblastoma spheroids.
Documented Applications
Treatment of multiple myeloma, diffuse large B-cell lymphoma, acute myeloid leukemia, and follicular lymphoma, with oral administration specified in a claim.
Treatment of solid tumors, including colorectal cancer, prostate cancer, and nasopharyngeal cancer.
Treatment of myelodysplastic syndrome.
Treatment of inflammatory disorders, including inflammatory bowel disease (Crohn's disease or ulcerative colitis) and collagen antibody-induced arthritis.
Treatment of cancer in combination with radiation, including treatment of non-small cell lung cancer.
Evaluation in cancer-cell growth assays, MDA-MB-468, Z-138, Hep3B, COLO 205, and MOLT 4 xenograft models, and U87MG and U251MG glioblastoma spheroids.
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