17-beta-hydroxywithanolides and use thereof in treating cancer
Inventors
Sayers, Thomas J. • Tewary, Poonam • Gunatilaka, Leslie • Brooks, Alan D. • Wijeratne, Kithsiri • Xu, Yaming
Assignees
University of Arizona • US Department of Health and Human Services
Publication Number
US-12018045-B2
Publication Date
2024-06-25
Expiration Date
2039-03-06
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Abstract
Disclosed are compounds suitable for enhancing cancer treatment, for example, a compound of formula (I): (I) wherein R1 is as defined herein. Also disclosed is a method of enhancing the response of cancer cells in a mammal to treatment with an apoptosis inducing ligand, a method of inducing apoptosis in cancer cells in a mammal, and a method of treating prostate cancer in mammal in need thereof comprising administration of a compound described herein.
Core Innovation
The invention provides compounds of formula (I) with variable substituent R1, suitable for enhancing cancer treatment by sensitizing cancer cells to apoptosis-inducing ligands. These compounds include various alkyl, cycloalkyl, aryl, heteroaryl, and other groups, optionally substituted with specific substituents. The invention further includes methods of synergistically enhancing the response of cancer cells to apoptosis-inducing ligands such as TRAIL or poly (I:C), and inducing apoptosis in cancer cells resistant to such ligands by administering these compounds.
The problem being solved arises from the toxicity and limited efficacy of existing death receptor ligands like Fas ligand and TNF-alpha. While TRAIL offers selective apoptosis of cancer cells with a better safety profile, many cancer cells exhibit resistance to TRAIL. Similarly, apoptosis signaling via TLR3 ligands like poly (I:C) is weak and requires long incubations. There is thus an unmet need for sensitizers that enhance cancer cell response to apoptosis-inducing ligands, overcoming resistance and improving therapeutic outcomes.
The inventive compounds sensitize cancer cells to apoptosis induced by exogenous ligands or those produced by anti-cancer T cells in immunotherapy. The invention includes synergistic methods combining the compounds with apoptosis-inducing ligands, immunotherapies, Smac mimetics, or Bcl-2 antagonists to overcome resistance. These methods can be applied to treat a variety of cancers, including prostate cancer, by reducing levels of anti-apoptotic proteins such as cFLIP, thereby enhancing the effectiveness of apoptosis-inducing treatments.
Claims Coverage
The patent contains two independent claims, focusing on the compound of formula (I) and pharmaceutical compositions comprising such compounds. The claims define the chemical structure of the compounds and their use in pharmaceutical formulations.
Compound composition defined by formula (I)
A compound of formula (I) wherein R1 is selected from C3-C8 cycloalkyl, C6-C10 aryl, C6-C10 aryl-C1-C10 alkyl, C6-C10 aryl-C2-C10 alkenyl, monocyclic heteroaryl, bicyclic heteroaryl, monocyclic heteroaryl-C1-C10 alkyl, bicyclic heteroaryl-C1-C10 alkyl, or 4-alkylenyl-tetrahydro-1H-thieno[3,4-d]imidazol-2(3H)-one. The aryl or heteroaryl portion of R1 is optionally substituted with alkyl, alkoxy, aryl, thioalkoxy, heterocyclyl, and nitro groups.
Pharmaceutical compositions comprising compounds of formula (I)
Pharmaceutical compositions comprising the compound of formula (I) or its specific embodiments with the defined R1 substituents, combined with a pharmaceutically acceptable carrier suitable for administration.
The claims cover novel compounds with specific chemical structures that sensitize cancer cells to apoptosis-inducing ligands and pharmaceutical compositions containing these compounds, establishing chemical and formulation scope for therapeutic use in cancer treatment.
Stated Advantages
The compounds selectively sensitize cancer cells to apoptosis-inducing ligands, including TRAIL and poly (I:C), thereby overcoming resistance in cancer therapies.
The compounds act synergistically with apoptosis-inducing ligands and other therapeutic agents like Smac mimetics and Bcl-2 antagonists, potentially reducing required doses and toxicity.
The compounds reduce cFLIP levels which is implicated in the inhibition of cancer cell proliferation, including in androgen-dependent and castrate-resistant prostate cancer cells.
The approach provides a more favorable safety profile compared to previous death receptor ligands that were too toxic for systemic anticancer use.
Documented Applications
Use of compounds to synergistically enhance the response of cancer cells in mammals to treatment with apoptosis-inducing ligands such as TRAIL, TNF-alpha, FasL, and TLR3 ligands like poly (I:C).
Methods of inducing apoptosis in cancer cells resistant to apoptosis-inducing ligands by administration of the compounds together with such ligands.
Treatment of various cancers including renal carcinoma, melanoma, prostate cancer, and others, through administration of the compounds alone or in combination with apoptosis-inducing ligands or immunotherapies.
Combination therapy with anti-cancer T cells producing apoptosis-inducing ligands to enhance tumor cell killing.
Use of the compounds in pharmaceutical compositions for administration via multiple routes including oral, parenteral, topical, aerosol, and suppositories.
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