Septin inhibitors for treatment of cancers
Inventors
Singh, Rakesh K. • KIM, Kyu K. • TURNER, Rachael • Moore, Richard G.
Assignees
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Publication Number
US-12433876-B2
Publication Date
2025-10-07
Expiration Date
Abstract
The present disclosure provides novel compounds, compositions, and methods for modulating one or more septin proteins, e.g., septin-2. Such compounds and compositions are useful for the treatment of a cancer, e.g., endometrial, pancreatic, lung, breast or ovarian cancer, such as serous and ovarian clear cell carcinoma.
Core Innovation
The invention relates to septin inhibitor compounds and pharmaceutically acceptable salts thereof for treating cancer by modulating septin expression and/or septin activity. The compounds include aryl ureas and diaryl urea-like structures, with specific compound series described including UR214 series compounds and forchlorfenuron (FCF) and FCF analogs, with optional exclusion of FCF.
Structure-activity results are presented showing that CF3S substitution on the phenyl ring generates potent cytotoxic activity, while replacing the 2-chloropyridine with 2-chloropyrimidine abolishes activity. The derivatives show dose-dependent anti-viability effects across ovarian and endometrial cancer cell lines, with apoptosis induction, inhibition of HER2 expression in ECC-1 and HCH-1 without affecting EGFR, and reduced HE4 secretion.
The disclosure also describes effects consistent with disrupting septin filaments, including septin filament catastrophe and decreased septin activity. It further links the activity to septin-2, notes that septin-2 knockdown decreases HER2 and HE4 and reduces viability, and references broader biological validation including associations of septin overexpression with cancer mortality using Kaplan-Meier/TCGA/HPA and mentions xenograft tumors and assays monitoring proliferation and apoptosis markers.
Claims Coverage
The independent claim is directed to a compound, or a pharmaceutically acceptable salt thereof, selected from specified options. The claim set covers four principal inventive features: compound selection, pharmaceutical composition with excipients, therapeutic administration to treat cancer, and optional combination therapy with additional therapeutic agents, including narrowing to enumerated cancer types.
Selected septin inhibitor compound or pharmaceutically acceptable salt
A compound selected from specified options, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition comprising the compound selected for the independent claim, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.
Treating cancer by administering a therapeutically effective amount
A method for treating cancer in a subject comprising administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.
Method for treating a selected cancer type from an enumerated group
The method of administering a therapeutically effective amount is applied to a selected cancer type chosen from a listed group, including any combination thereof.
Optional combination therapy with one or more additional therapeutic agents
The method further includes administering one or more additional therapeutic agents in addition to the compound.
Combination therapy with a taxane or an anti-HER2 antibody
The additional therapeutic agents are selected from a group consisting of a taxane, paclitaxel, an anti-HER2 antibody, or trastuzumab.
Across the claim coverage, the main inventive concept is a selected septin inhibitor compound, or pharmaceutically acceptable salt, used as a therapeutically effective agent for cancer treatment, including formulated pharmaceutical compositions, enumerated cancer indications, and optional combination therapy with specified additional therapeutic agents.
Stated Advantages
Potent cytotoxic activity for CF3S substitution on the phenyl ring, with reported abolition of activity by replacing 2-chloropyridine with 2-chloropyrimidine.
Dose-dependent anti-viability effects across ovarian and endometrial cancer cell lines.
Apoptosis induction, reported to be more pronounced for UR214-9 than UR214-7.
Inhibition of HER2 expression in ECC-1 and HCH-1 without affecting EGFR.
Reduction of HE4 secretion.
Septin-2 linkage supported by septin-2 knockdown effects on HER2, HE4, and viability.
Documented Applications
Anti-viability and apoptosis evaluation in ovarian and endometrial cancer cell lines using MTS and BrdU assays.
Modulation of HER2 expression in ECC-1 and HCH-1 and reduction of HE4 secretion, associated with septin-2 activity.
Biological validation of septin overexpression associations with cancer mortality using Kaplan-Meier/TCGA/HPA.
Treating cancer in a subject by administering a therapeutically effective amount of the compound, or pharmaceutically acceptable salt.
Cancer types explicitly enumerated for treatment include pancreatic cancer, breast cancer, lung cancer, kidney (renal) cancer, liver cancer, ovarian cancer, and endometrial cancer, with additional listed cancer types also included and any combination thereof.
Combination therapy use cases include administering the compound together with one or more additional therapeutic agents, including paclitaxel and trastuzumab.
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