Hydrazide containing nuclear transport modulators and uses thereof
Inventors
Sandanayaka, Vincent P. • Shacham, Sharon • McCauley, Dilara • Shechter, Sharon
Assignees
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Publication Number
US-11034660-B2
Publication Date
2021-06-15
Expiration Date
Abstract
The invention generally relates to nuclear transport modulators, e.g., CRM1 inhibitors, and more particularly to a compound represented by structural formula I: or a pharmaceutically acceptable salt thereof, wherein the values and alternative values for the variables are as defined and described herein. The invention also includes the synthesis and use of a compound of structural formula I, or a pharmaceutically acceptable salt or composition thereof, e.g., in the treatment, modulation and/or prevention of physiological conditions associated with CRM1 activity.
Core Innovation
The disclosure relates to hydrazide-containing compounds and salts, including triazole-containing CRM1 nuclear-export inhibitors such as compound I-3 and analogues I-4 through I-26. A reported synthetic route favors Z-selective olefin formation via a Z-acrylic acid intermediate, thereby reducing reliance on inefficient E/Z isomer separation. The disclosed compounds exhibit CRM1 inhibition, high in vivo exposure, relatively low brain penetration, and cytotoxic activity.
The patent provides a method for treating multiple myeloma in a subject in need thereof. The method comprises administering a therapeutically effective amount of compound I-3, or a pharmaceutically acceptable salt thereof, in combination with bortezomib, dexamethasone, or both. Associated claim elements define options for separate dosage forms, administration at the same time, and oral administration of compound I-3.
Compound I-3 demonstrates dose-dependent inhibition of triple-negative breast cancer xenograft growth and induces apoptosis and nuclear localization of tumor-suppressor proteins. In addition, compound I-4 demonstrates activity in arthritis and psoriasis models and influences novel-object recognition, food intake, and weight gain in obese Zucker rats. The compounds are reported to be tolerated in tested models.
Claims Coverage
The claims include one independent claim directed to a combination method for treating multiple myeloma, comprising one inventive feature.
Treatment of multiple myeloma with compound I-3 and an additional therapeutic agent
A method for treating multiple myeloma in a subject in need thereof comprising administering a therapeutically effective amount of compound I-3, or a pharmaceutically acceptable salt thereof, together with an additional therapeutic agent selected from bortezomib, dexamethasone, or a combination thereof. Related claim elements specify separate dosage forms, administration at the same time, and oral administration of compound I-3.
The claim coverage focuses on the combination treatment of multiple myeloma using compound I-3, or a pharmaceutically acceptable salt thereof, with bortezomib, dexamethasone, or both, with dependent claims further refining dosage forms, timing, and administration routes.
Stated Advantages
The compounds are reported to provide high in vivo exposure alongside low brain penetration.
The reported synthetic advance favors Z-selective olefin formation and reduces reliance on inefficient E/Z isomer separation.
The experimental data report inhibition of triple-negative breast cancer xenograft growth, cytotoxicity in breast cancer cell lines, and induction of apoptosis in sensitive cells.
The experimental data report reduced arthritis scores and psoriasis-associated ear inflammation, along with trends toward improved novel-object recognition and reduced food intake and weight gain.
The compounds are reported to be tolerated in tested models.
Documented Applications
Treatment of multiple myeloma in a subject in need thereof using compound I-3, or a pharmaceutically acceptable salt thereof, together with bortezomib, dexamethasone, or a combination thereof.
Modulation of CRM1 (exportin-1/XPO1)-mediated nuclear export for disorders associated with abnormal nuclear transport.
Evaluation of compound I-3 in breast-cancer cell lines and triple-negative breast cancer xenograft models.
Evaluation of compound I-4 in mouse models of arthritis and psoriasis-associated ear inflammation.
Evaluation of compound I-4 for effects on novel-object recognition, food intake, and weight gain in obese Zucker rats.
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