Autophagy modulators for use in treating cancer
Inventors
DePamphilis, Melvin L. • Sharma, Gaurav • Marugan, Juan Jose • Ferrer, Marc • Roy, Ajit
Assignees
US Department of Health and Human Services
Publication Number
US-11471460-B2
Publication Date
2022-10-18
Expiration Date
2038-11-28
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Abstract
Disclosed is method for treating cancer in a mammal, comprising administering to a mammal in need thereof a compound of the formula: wherein R1, R2, and R3 are as defined herein, wherein the cancer is an autophagy-dependent cancer, in an amount sufficient to induce autophagy in the cell and cause the death of cancer cells. Also disclosed is a method for selectively killing cancer cells in a patient afflicted with cancer, comprising administering to the mammal, wherein the cancer cells are autophagy-dependent cancer cells, in an amount sufficient to induce autophagy in the cells and cause the death of the cancer cells.
Core Innovation
The invention provides a method for treating cancer in a mammal by administering a compound or salt of a specific chemical formula that inhibits autophagy in autophagy-dependent cancer cells, thereby causing the death of cancer cells. The compounds disrupt lysosome homeostasis by inhibiting lysosome fission without preventing lysosome fusion, impairing trafficking of molecules into lysosomes without altering their acidity, and inhibiting fusion between lysosomes and autophagosomes, which blocks autophagic flux. These actions selectively inhibit proliferation and reduce the viability of autophagy-dependent cancer cells while sparing autophagy-independent normal cells.
The background identifies the problem that many cancers depend on autophagy for survival and proliferation, making autophagy a therapeutic target. Existing therapies focus on inhibiting autophagy using chloroquine and derivatives, which act by decreasing lysosomal acidity to impair autophagy-mediated survival. However, cancer cells can survive acidic stress by upregulating autophagy, and chloroquine-based therapies might be ineffective in acidic tumor microenvironments. This creates an unmet need for therapies that can selectively disrupt autophagy in autophagy-dependent cancer cells by targeting multiple aspects of lysosome homeostasis.
Claims Coverage
The patent contains one independent claim encompassing methods for treating autophagy-dependent cancer or selectively killing autophagy-dependent cancer cells by administering defined chemical compounds.
Methods for treating autophagy-dependent cancer by administering specified compounds
Administering to a mammal in need an effective amount of a compound or pharmaceutically acceptable salt of a defined chemical formula that inhibits autophagy and causes the death of autophagy-dependent cancer cells. The chemical formula includes variations in substituents R1, R2, R3, and X, allowing formation of morpholinyl rings or heterocyclyl rings, with specific examples and tautomeric forms included.
Methods for selectively killing autophagy-dependent cancer cells using specified compounds
Administering to a patient an effective amount of a compound or pharmaceutically acceptable salt of the same defined formula as above to selectively inhibit autophagy and cause death of autophagy-dependent cancer cells, including those with specific cancer types and BRAFV600E mutation.
The claims cover administration of chemically defined compounds that selectively inhibit autophagy in autophagy-dependent cancers by disrupting lysosome homeostasis, thereby treating or selectively killing cancer cells, including cancers bearing specific mutations or types.
Stated Advantages
The compounds rapidly and selectively disrupt multiple events in lysosome homeostasis, including inhibition of lysosome fission, impairment of molecular trafficking into lysosomes without altering acidity, and blocking of lysosome-autophagosome fusion.
They bind specifically and with high affinity to the PIKFYVE phosphatidylinositol kinase, a key regulator of lysosome function.
They selectively inhibit proliferation and reduce viability of autophagy-dependent human cancer cells while sparing normal human cells.
They demonstrate enhanced therapeutic potential compared to existing autophagy inhibitors such as hydroxychloroquine and chloroquine, with up to 1000-fold greater efficacy in certain cancer cells.
They inhibit tumor formation and progression in vivo in melanoma xenograft models without observable ill effects.
Documented Applications
Treatment of autophagy-dependent cancers including breast cancer, malignant melanoma, colorectal carcinoma, thyroid papillary carcinoma, glioma, ovarian serous carcinoma, lung adenocarcinoma, and hairy cell leukemia.
Selective killing of autophagy-dependent cancer cells, particularly those harboring the BRAFV600E mutation.
Use alone or in combination with established anticancer therapies to improve efficacy of cancer treatment.
Treatment of malignant or metastatic cancer forms dependent on autophagy.
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