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Publication Number
US-11485732-B2
Publication Date
2022-11-01
Expiration Date
Abstract
The present disclosure features compounds useful for the treatment of BAF complex-related disorders.
Core Innovation
The disclosure provides compounds that inhibit and/or modulate BRG1 and/or BRM in the SWI/SNF (BAF) chromatin remodeling complex. The compounds are described as compounds having a defined chemical structure, or pharmaceutically acceptable salts thereof, including labeled/isotopic variants. The document frames the therapeutic approach as decreasing BAF complex activity by targeting BRG1 and/or BRM.
The described material includes preparation of the disclosed compounds, pharmaceutical compositions, and pharmaceutically acceptable salts/excipients. The partial content describes BRG1/BRM ATPase inhibitors and lead compounds exemplified by a methylsulfonyl-containing pyrrole-3-carboxamide with a cis-2,6-dimethylmorpholine motif.
Biological activity is provided using ATPase catalytic activity assay data, cell growth inhibition, apoptosis, and in vivo xenograft tumor growth inhibition results. The disclosure also states that the compounds reduce tumor growth and metastatic colonization and include therapeutic scope for cancer and viral infection.
Claims Coverage
The claim coverage centers on compounds having specified chemical structures or pharmaceutically acceptable salts thereof. The provided claim set also includes therapeutic methods for cancer and viral infection, with dependent claims addressing genetic alteration-defined and treatment-refractory cancer populations.
Structural compound definition for BRG1/BRM inhibition
A compound having the structure, or a pharmaceutically acceptable salt thereof.
Treating cancer by administering the compound
A method of treating cancer in a subject by administering an effective amount of the compound having the structure, or a pharmaceutically acceptable salt thereof.
Cancer characterized by specified genetic alterations
The method is practiced where the cancer has or has been determined to have one or more specified genetic alterations, including KRAS, GNAQ, GNA11, PLCB4, CYSLTR2, BAP1, SF3B1, EIF1AX mutations, TFE3/TFEB/MITF translocations, and/or EZH2/SUZ12/EED mutations.
Treatment of cancer resistant to prior anticancer therapy
The method is applied to cancer that is resistant to or has failed to respond to prior anticancer therapy.
Treating viral infection by administering the compound
A method of treating a viral infection by administering an effective amount of the compound having the structure, or a pharmaceutically acceptable salt thereof, to a subject in need of treatment.
Overall, the claim coverage is anchored by structurally defined compounds and pharmaceutically acceptable salts, with further coverage directed to therapeutic methods for cancer, including genetically defined and treatment-refractory populations, and to treating viral infection by administering an effective amount of the compound.
Stated Advantages
Exhibits ATPase catalytic activity inhibition with reported IP50 values against BRM and BRG1.
Provides cell growth inhibition across multiple cancer cell lines with reported GI50/IC50 values.
Provides in vivo xenograft tumor growth inhibition with tolerability data [procedural detail omitted for safety].
Inhibits and/or modulates BRG1 and/or BRM in the SWI/SNF (BAF) chromatin remodeling complex.
Decreases BAF complex activity.
Induces apoptosis.
Reduces tumor growth.
Reduces metastatic colonization.
Supports treatment of BRG1 loss-of-function mutation-related cancers.
Supports treatment of viral infection.
Documented Applications
Treating cancer in a subject by administering an effective amount of the compound.
Treating cancer characterized by specified genetic alterations, including KRAS, GNAQ, GNA11, PLCB4, CYSLTR2, BAP1, SF3B1, EIF1AX mutations, TFE3/TFEB/MITF translocations, and/or EZH2/SUZ12/EED mutations.
Treating cancer that is resistant to or has failed to respond to prior anticancer therapy.
Treating a viral infection by administering an effective amount of the compound to a subject in need of treatment.
Treatment of cancer, including cancer subtypes and metastatic disease, by administering an effective amount of the disclosed compounds.
Uveal melanoma and hematological cancers are referenced in the partial content alongside provided biological activity data.
In vivo xenograft tumor growth inhibition is documented [procedural detail omitted for safety].
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