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Assignees
Member
University of Nevada, Las VegasThe University of Nevada, Las Vegas is a public research university offering comprehensive undergraduate, graduate, and professional programs. The institution is recognized for research initiatives, interdisciplinary curriculum, community partnerships, and diverse student support. UNLV provides resources spanning financial assistance, technology, career development, outreach, and research, advancing individual achievement and community engagement in a multicultural environment.
The University of Nevada, Las Vegas is a public research university offering comprehensive undergraduate, graduate, and professional programs. The institution is recognized for research initiatives, interdisciplinary curriculum, community partnerships, and diverse student support. UNLV provides resources spanning financial assistance, technology, career development, outreach, and research, advancing individual achievement and community engagement in a multicultural environment.
Publication Number
US-9918983-B2
Publication Date
2018-03-20
Expiration Date
Abstract
Disclosed are inhibitors of lysine-specific demethylase I (LSD1); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating cancers characterized by the presence of Sox2 using the compounds and compositions Also disclosed are methods of treating cancers characterized by the presence of Sox2 using inhibitors of LSD1 and/or histone deacetylation I (HDAC1). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
Core Innovation
The disclosure describes substituted trans-cyclopropanes and LSD1 inhibitor compounds having a structure represented by a formula with variable substituents R1, Ar1, and optional Cy1 and Ar2, together with pharmaceutically acceptable salts. The phenyl portion Ar1 is substituted with selected functional groups, including —OR12, —C(O)SR17, —CONR19aR19b, and —SO2NR20aR20b, and the document includes selected formula structures shown in the claim images.
The therapeutic and biological uses include cancer treatment, including inhibition of LSD1 and/or HDAC1 in Sox2-expressing cancers, cancer stem cells, and cancer-initiating cells. The disclosure links LSD1/HDAC1 activity to histone methylation and histone acetylation events, including H3K4me1/2, H3K9me2, and H4K16 acetylation, and describes inhibition of proliferation and/or survival of cancer cells.
The document also includes therapeutic methods and kits that use an LSD1 inhibitor and addresses cancers in which Sox2-expressing cells are present, including situations involving Sox2 gene amplification at 3q22.33. It further describes formulation, administration, and kit concepts, together with selected compound examples and compound classes such as tranylcypromine and 2-PCPA.
Claims Coverage
The consolidated claim coverage centers on a structural chemical definition with explicit substituent selections for R1, Ar1, optional Ar2 and Cy1, and additional variable groups including R12, R21, R17, R19a, R19b, R20a, and R20b. The dependent claims further narrow this space by restricting R1 to butyl isomers, limiting the count of specific phenyl substituents, constraining allowed alkyl options, and including selected formula structures shown in the claim images.
Substituted compound structure defined by variable substituents
A compound having a structure represented by a formula, wherein R1 is selected from C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 hydroxyalkyl, Ar1, and Cy1; Ar2, when present, is selected from aryl and heteroaryl with specified substitution rules; and Cy1, when present, is selected from C3-C6 cycloalkyl and C2-C5 heterocycloalkyl with specified substitution rules.
Phenyl functionalization of Ar1 using specified group options
Ar1 is phenyl substituted with 1, 2, or 3 groups independently selected from —OR12, —C(O)SR17, —CONR19aR19b, and —SO2NR20aR20b; R12, when present, is —CO2R21; and R21, when present, is selected from hydrogen and C1-C4 alkyl.
Independent selection rules for R17, R19a, R19b, R20a, and R20b
Each of R17, R19a, R19b, R20a, and R20b, when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl.
Pharmaceutically acceptable salt coverage
The compound includes a pharmaceutically acceptable salt thereof.
Refined R1 selection to butyl isomers
R1 is selected from n-butyl, i-butyl, s-butyl, or t-butyl.
Refined phenyl substitution count for —OCO2R21
Ar1 is phenyl substituted with 1, 2, or 3 —OCO2R21 groups.
Refined R21 selection to specific alkyl groups
R21, when present, is selected from n-propyl, propyl, n-butyl, i-butyl, s-butyl, or t-butyl.
Refined multi-variable substituent set for R17, R19a, R19b, R20a, and R20b
Each of R17, R19a, R19b, R20a, and R20b, when present, is independently chosen from hydrogen, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl.
Compound defined by selected chemical formula structures
The compound is defined as having a structure represented by one of several selected chemical formulas shown in the claim images.
The claim coverage is anchored in a structural chemical definition with explicit substituent selections for R1, Ar1, optional Ar2 and Cy1, and additional variable groups including R12, R21, R17, R19a, R19b, R20a, and R20b. The dependent claims further narrow this space by restricting R1 to butyl isomers, limiting the count of specific phenyl substituents, constraining allowed alkyl options, and including selected formula structures shown in the claim images.
Stated Advantages
Inhibition of proliferation and/or survival of cancer cells by administering or contacting with LSD1 inhibitors and/or HDAC1 inhibitors.
Epigenetic regulation of histone methylation and histone acetylation events associated with Sox2-expressing tumors.
Sox2-dependent growth suppression in Sox2-expressing cancers.
Selective potency in Sox2-expressing cells.
Selective growth inhibition and G1 cell-cycle arrest.
Documented Applications
Treatment of cancer, including Sox2-expressing tumors and cancer stem cells or cancer-initiating cells.
Modulating histone methylation events by contacting cells with compounds that inhibit LSD1 and/or HDAC1.
Pharmaceutical compositions, medicament manufacture, and kit concepts including LSD1 and/or HDAC1 inhibitors and anticancer therapeutic agents.
Use in cancers, carcinomas, and squamous cell carcinomas.
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