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-11787771-B2
Publication Date
2023-10-17
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 invention relates to a method for treating a disorder associated with CRM1 activity by administering to a subject in need thereof a therapeutically effective amount of a compound represented by a specified structural formula, or a pharmaceutically acceptable salt thereof. The compounds are positioned as nuclear export inhibitors targeting CRM1 activity, with biological activity consistent with CRM1 inhibition and CRM1-related effects.
The disclosure includes Formula I embodiments and related hydrazide, amide, acrylic acid, acrylate, triazole-containing, and substituted benzothioamide/triazole derivatives, with stereochemical variants such as (E)/(Z) and cis/trans isomeric forms. The disclosure also includes pharmaceutically acceptable salts, compositions, example compound structures, and characterization information for the disclosed compounds.
The therapeutic scope includes cancer and other CRM1-mediated disorders, with links to tumor suppressor and growth regulator nuclear retention and to signaling pathways involving NF-baB/IkB, HIF1, RXRb1, p53/p73, p21, pRB, p27, c-Abl, and FOXO proteins. The disclosure further includes neurodegenerative/neuroprotective contexts, viral diseases dependent on CRM1-mediated nuclear export, and triple-negative breast cancer, with in vivo tumor growth inhibition and biomarker responses in TNBC cell lines.
The disclosure addresses pharmacokinetic behavior in vivo, including AUC_inf and brain-to-plasma exposure observations, and reports unexpected high brain exposure with relatively low brain-to-plasma ratios. It also references target in vivo PK ranges and blood-brain barrier considerations.
Claims Coverage
The consolidated claim coverage centers on administering a therapeutically effective amount of a compound represented by a specified structural formula, or a pharmaceutically acceptable salt thereof, to treat a disorder associated with CRM1 activity. The identified inventive features further refine the treated disorders, route of administration, and combination therapy, for a total of five inventive features.
Method for treating a disorder associated with CRM1 activity
Administering to a subject in need thereof a therapeutically effective amount of a compound represented by the structural formula or a pharmaceutically acceptable salt thereof.
Treating a selected hematologic disorder
The method treats a disorder selected from myelodysplastic syndrome or a myeloproliferative disorder.
Treating selected cancers
The method treats cancer selected from colon cancer, lung cancer or brain cancer.
Combination therapy for cancer
Administering the compound together with a second therapeutic useful for treating cancer.
Oral administration
Performing the method by orally administering the compound.
Across the consolidated claim set, the core claimed coverage is CRM1-activity associated disorder treatment using a specified structural formula compound or pharmaceutically acceptable salt, with dependent features directed to myelodysplastic syndrome or myeloproliferative disorder, selected cancers, oral administration, and combination therapy with a second cancer therapeutic.
Stated Advantages
High in vivo exposure (AUC) with low brain penetration.
Allows treatment of a disorder associated with CRM1 activity.
Reports dose-dependent tumor growth inhibition and tolerance in a TNBC xenograft setting and biomarker responses consistent with CRM1-related pathway effects.
Reports unexpected high brain exposure with relatively low brain-to-plasma ratios for Formula I compounds.
Achieves pharmacokinetic properties and nuclear export inhibition characterized by target in vivo PK ranges using AUC_inf and brain-to-plasma (B:P) ratio relative to prior nuclear export inhibitors.
Supports brain exposure considerations linked to blood-brain barrier (BBB) using reported brain-to-plasma (B:P) ratio metrics.
CRM1 (RevGFP) nuclear export inhibition is described in the partial content.
Documented Applications
Therapeutic treatment of CRM1-associated disorders, including contexts involving nuclear retention of tumor suppressors and growth regulators.
Treatment for inflammatory and autoimmune diseases involving NF-baB/IkB, HIF1, and RXRb1 pathways.
Treatment in neurodegenerative/neuroprotective contexts.
Treatment of viral infections dependent on CRM1-dependent nuclear export, including HIV-1 via Rev/RRE transport and dengue via CRM1-dependent NS5 export.
Medicaments, including medicament manufacturing and use claims, for treating CRM1-associated disorders.
Treatment of myelodysplastic syndrome or a myeloproliferative disorder.
Treatment of cancers selected from colon cancer, lung cancer, or brain cancer.
Triple-negative breast cancer (TNBC) treatment context including in vivo xenograft efficacy and in vitro potency/biomarker responses for CRM1 inhibition-associated effects.
Arthritis model efficacy, including CAIA (monoclonal-antibody induced arthritis) within the described in vivo studies.
Psoriasis model efficacy, including a PMA ear model within the described in vivo studies.
Novel object recognition within the described in vivo studies.
Obese Zucker rat feeding/study outcomes for Compound I-4 within the described in vivo studies.
CRM1 (RevGFP) nuclear export inhibition assay usage and cytotoxicity evaluation in multiple myeloma cells as described in the partial content.
Pharmacokinetics reporting including brain-to-plasma ratios for compounds of Formula I and comparator structures as described in the partial content.
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