Englerin derivatives for treatment of cancer
Inventors
Beutler, John A. • Echavarren, Antonio • Chain, William • Beech, David • Wu, Zhenhua • Suppo, Jean-Simon • BRAVO, Fernando • Rubaiy, Hussein
Assignees
Institut Catala dInvestigacio Quimica ICIQ • Universitat Rovira i Virgili URV • University of Leeds • United States, REPRESENTED BY SECRETARY Department Of Health And Human Sciences AS • University of Delaware • US Department of Health and Human Services
Publication Number
US-11098054-B2
Publication Date
2021-08-24
Expiration Date
2038-07-05
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Abstract
Disclosed is a compound of formula (I) in which a, R1-R5 and X1 are as described herein. Also disclosed are a pharmaceutical composition containing the compound and a method of using the compound for treating cancer, such as renal cancer.
Core Innovation
The invention provides compounds of formula (I), which are englerin derivatives with specific structural variables defined for groups a, R1-R5, and X1. These compounds are therapeutically active and can be formulated into pharmaceutical compositions for treating cancer. A key aspect of the invention is the discovery that these compounds can kill cancer cells, particularly renal cancer cells, without the toxicity associated with prior englerin compounds that act as TRPC4 agonists.
Cancer, especially renal cancer, poses significant treatment challenges due to incomplete therapeutic responses and side effects of existing therapies. Natural products like englerin A and B, isolated from the Phyllanthus engleri plant, have been studied as potential cancer therapeutics. Englerin A activates protein kinase C theta (PKCθ) and TRPC ion channels, leading to cancer cell cytotoxicity, but also causes lethal side effects, such as toxicity in rodents at effective doses.
The problem addressed by this invention is the unmet need for englerin derivatives that effectively kill cancer cells, especially those cancer cells associated with PKCθ, while reducing toxicity. It was surprisingly found that compounds of formula (I) are therapeutically active in killing cancer cells despite being inactive as TRPC4 agonists. This indicates a different mechanism and suggests lower toxicity in subjects, offering a novel therapeutic approach for cancer treatment.
Claims Coverage
The claims include one independent claim directed to a compound of formula (I) and one independent claim directed to a method of treating cancer with such compounds. The inventive features are centered on the specific chemical structure of the compounds and their use in cancer treatment.
Compound of formula (I) with defined substituents
The compound is defined by formula (I) wherein 'a' is a single or double bond; R1 is C3-C6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted; R2 is selected from hydroxy, alkoxy, and specific radicals involving X2 and X3 (O, S, or NR groups); R3 and R4 are C1-C6 alkyl; R5 is selected from certain alkylated or alkenylated groups with possible cycloalkyl or aryl substituents; X1 is selected from O, NR15, and S; and integers n and m define substitution numbers, with constraints when 'a' is double bond that R1 must be heterocycloalkyl.
Pharmaceutical compositions containing compounds of formula (I)
Pharmaceutical compositions comprising a pharmaceutically acceptable carrier and the compound or a pharmaceutically acceptable salt thereof as defined in the first inventive feature.
Method of treating cancer using compounds of formula (I)
A method for treating cancer in a subject by administering an effective amount of the compound of formula (I) or its pharmaceutically acceptable salt. The method covers treatment of various cancers including leukemia, non-small cell lung cancer, colon cancer, melanoma, prostate cancer, renal cancer, bladder cancer, breast cancer, CNS cancer, ovarian cancer, and Ewing's sarcoma, with a preference for renal cancer.
Compounds with reduced activation of TRPC4 and TRPC5
Compounds of formula (I) that have little or no activation (agonism) of TRPC4 or TRPC5 ion channels, in contrast to englerin A, resulting in reduced lethality and toxicity when used for cancer treatment.
The claims cover novel englerin-derived compounds defined by formula (I) with specific substituents, their pharmaceutical compositions, and therapeutic methods for treating cancer. The claims emphasize compounds' selectivity with reduced TRPC4 activation, enabling effective cancer cell killing with reduced side effects.
Stated Advantages
The compounds of formula (I) are therapeutically active against cancer cells while being less toxic due to the lack of TRPC4 agonism.
The compounds provide effective treatment especially for renal cancer, overcoming deficiencies in current therapies with incomplete responses and side effects.
Documented Applications
The compounds are used for treating cancer, including but not limited to leukemia, non-small cell lung cancer, colon cancer, melanoma, prostate cancer, renal cancer, bladder cancer, breast cancer, central nervous system cancer, ovarian cancer, and Ewing's sarcoma.
Pharmaceutical compositions comprising the compounds for oral, intravenous, topical, parenteral, aerosol, and other routes of administration to treat cancer patients.
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