Chromenopyridine-based compounds and methods of making and use thereof
Inventors
Mayor, June A • Patil, Shivaputra A. • Kaplan, Ronald S.
Assignees
Rosalind Franklin University of Medicine and Science
Publication Number
US-11814392-B2
Publication Date
2023-11-14
Expiration Date
2041-10-29
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Abstract
Chromenopyridine-based compounds are provided. In one aspect, the present disclosure provides a method for treating cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of a chromenopyridine-based compound to the subject. A representative compound is 2,4-diamino-7,8-dimethoxy-5-((4-methoxyphenyl)thio)-5H-chromeno[2,3-b]pyridine-3-carbonitrile (Compound 1).
Core Innovation
The present disclosure relates to chromenopyridine-based compounds for the treatment of cancer. These compounds are defined by formula (I), allowing various substitutions at designated positions, and pharmaceutical compositions including these compounds or their pharmaceutically acceptable salts. The inventions further provide methods of making these chromenopyridine analogs using efficient and modular synthetic procedures.
The invention addresses the problem that, despite advances in cancer treatment, it remains highly challenging due to tumor heterogeneity, toxicity, and multidrug resistance. Cancer cell proliferation is driven by dysregulated metabolic processes, with PMCT (plasma membrane citrate transporter, SLC13A5) being a key target for pharmacologic therapy. PMCT regulates cellular metabolism, and its inhibition has been shown to halt hepatocellular carcinoma cell growth by disrupting energy homeostasis. However, prior to this invention, therapeutic use of PMCT-targeting small molecules had not advanced to clinical trials.
This disclosure provides novel chromenopyridine compounds that inhibit PMCT and exhibit cytotoxic or anti-proliferative activity against a broad range of cancer cell lines. The invention specifically includes methods for treating cancer in subjects in need thereof by administering a therapeutically effective amount of these chromenopyridine-based compounds. Representative compounds, such as 2,4-diamino-7,8-dimethoxy-5-((4-methoxyphenyl)thio)-5H-chromeno[2,3-b]pyridine-3-carbonitrile (Compound 1), have demonstrated dose-dependent PMCT inhibition and significant anti-proliferative effects.
Claims Coverage
There are three independent claims in the patent, each defining a main inventive feature: a chromenopyridine-based compound of formula (I), a specific chromenopyridine compound or its salt, and a method of treating cancer using these compounds.
Chromenopyridine-based compound of formula (I)
The invention covers compounds defined by formula (I): - The structure comprises a chromenopyridine core with various possible substituents at R1, R2, R3, R4, R5, and RA. - R1 is selected from —OH, —O—(C1-C4 alkyl), or —S—(C1-C4 alkyl). - R2, R3, and R5 are independently H, —OH, or —O—(C1-C6 alkyl). - R4 is —OH, (C1-C2 alkyl), —O—(C1-C6 alkyl), or —N—(CH2CH3)2. - Each RA is independently H or CH3. - The compound includes any pharmaceutically acceptable salt thereof.
Specific chromenopyridine compound or pharmaceutically acceptable salt thereof
The invention claims a compound or its pharmaceutically acceptable salt having the structure: - A specified structure shown in the patent for particular analogs, such as 2,4-diamino-7,8-dimethoxy-5-((4-methoxyphenyl)thio)-5H-chromeno[2,3-b]pyridine-3-carbonitrile (Compound 1) and closely related analogs specifically described and exemplified.
Method of treating cancer using chromenopyridine compounds
The invention covers a method for treating cancer in a subject in need thereof, comprising: - Administering a therapeutically effective amount of a chromenopyridine-based compound as defined in the patent (formula (I) or specified analog) or a pharmaceutically acceptable salt thereof. - The cancers explicitly covered include leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, or hepatocellular carcinoma. - The compound is administered in a dosage in the range of 0.1 mg/kg to 400 mg/kg.
In summary, the patent claims cover chromenopyridine-based compounds of specified structure and salts, particular exemplified structures, and methods of treating various cancers by administering these compounds.
Stated Advantages
The compounds possess excellent PMCT (plasma membrane citrate transporter) inhibition activity, which is significant for cancer treatment.
The disclosed compounds show significant anti-proliferative activity against a broad panel of human cancer cell lines, with low micromolar or sub-micromolar GI50 values in several cancers.
Inhibition of PMCT by the compounds is dose-dependent, and leads to upregulation of AMPK and inhibition of lipogenesis and mTORC1 pathways, resulting in effective inhibition of cancer cell proliferation.
GI50 values of less than 1 μM were observed in multiple cancer cell lines, indicating potent anti-cancer effects.
Documented Applications
Use of chromenopyridine-based compounds for the treatment of cancer, including leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, hepatocellular carcinoma, and breast cancer.
Pharmaceutical compositions containing chromenopyridine-based compounds or salts thereof for administration to subjects in need of cancer therapy.
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