Hsp90β selective inhibitors
Inventors
Assignees
University of Kansas • University of Notre Dame
Publication Number
US-12030867-B2
Publication Date
2024-07-09
Expiration Date
2039-05-30
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Abstract
Described are compounds of formula (I), based on an isoquinolin-1(2H)-one backbone, that function as Hsp90β selective inhibitors. Also described are pharmaceutical compositions thereof and methods of treating cancer by administering compounds of formula (I).
Core Innovation
The invention describes novel compounds based on an isoquinolin-1(2H)-one backbone that function as selective inhibitors for the Hsp90β isoform. These compounds are defined by formula (I) and can exist as pharmaceutically acceptable salts. The patent also provides pharmaceutical compositions containing these compounds and methods of treating diseases by their administration.
The problem being addressed is that prior Hsp90 inhibitors, which are promising anti-cancer agents, lack efficacy in clinical translation and induce unwanted side effects, such as off-target toxicities and activation of the pro-survival heat shock response. These side effects are largely due to the lack of selectivity among the Hsp90 isoforms. Thus, there is a need for new Hsp90 inhibitors that provide enhanced selectivity, efficacy, and fewer adverse effects.
The core innovation solves this by offering Hsp90β-selective inhibitors that show increased binding affinity and selectivity for Hsp90β compared to other isoforms. These compounds degrade Hsp90β-dependent client proteins without inducing the heat shock response and demonstrate effective inhibition of cancer cells at low nanomolar concentrations. The patent further details the structure-activity relationship, specific substituents at various positions of formula (I), and the synthesis and evaluation of optimized analogs for improved selectivity and pharmacological properties.
Claims Coverage
The patent includes five main independent inventive features that define the scope of the invention.
Isoquinolin-1(2H)-one Hsp90β selective inhibitor compounds
A compound of formula (I), or a pharmaceutically acceptable salt thereof, where: - The isoquinolin-1(2H)-one core is substituted at R1 and R2 (hydrogen, halogen, or cyano, with R2 absent when the double bond is present), R3 (C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 heteroalkyl, C3-C8 heterocycle, C1-C6 hydroxyalkyl, C2-C6 alkynyl or alkenyl, C1-C6 haloalkyl, or alkylamino), and Y1-Y4 (varied as described) with additional substitution options for aryl, heteroaryl, cycloalkyl, or heterocycle. - The compound demonstrates selectivity for the Hsp90β isoform.
Pharmaceutical compositions comprising isoquinolin-1(2H)-one Hsp90β selective inhibitors
A pharmaceutical composition comprising: - A compound of formula (I) or its pharmaceutically acceptable salt, - And a pharmaceutically acceptable carrier.
Method of inhibiting Hsp90 using the compound
A method comprising: - Contacting Hsp90, including the Hsp90β isoform, with an effective amount of a compound of formula (I) or its pharmaceutically acceptable salt, - Resulting in inhibition of Hsp90.
Method of treating disease or disorder by administering the compound
A method for treating a disease or disorder in a subject in need thereof, comprising: - Administering a therapeutically effective amount of the compound of formula (I), or its pharmaceutical composition, to the subject, - Wherein the disease or disorder is specified as cancer, viral disease, anti-inflammatory disease, angiogenesis-related disease, chemotherapy-induced toxicity, or a protein misfolding or aggregation disease.
Treatment and specificity of cancer types
The compounds and methods cover treatment of: - Various cancers, including carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, seminoma, and cancers of specific tissues (bladder, blood, bone, brain, breast, cervix, colon/rectum, endometrium, head and neck, kidney, liver, lung, muscle tissue, ovary, pancreas, prostate, skin, spleen, stomach, testicle, thyroid, or uterus). - Certain claims further specify leukemia, and colon, breast, bladder, prostate, or kidney cancer.
The inventive features collectively claim a novel class of Hsp90β selective inhibitors, their pharmaceutical compositions, methods of Hsp90 inhibition, and methods of treating a range of diseases using these compounds, with particular emphasis on selective therapeutic targeting of Hsp90β-related conditions including various cancers.
Stated Advantages
The compounds provide increased affinity and selectivity for binding Hsp90β while also offering enhanced cellular efficacy over previously reported Hsp90 inhibitors.
Compounds induce degradation of Hsp90β-dependent clients without concomitant induction of Hsp90 and the pro-survival heat shock response.
The compounds demonstrate selectivity towards cancer cell lines and can inhibit cancer at low nanomolar concentrations comparable to Hsp90 inhibitors undergoing clinical trials.
Isoform-selective inhibition achieved by these compounds may overcome the liabilities associated with pan-Hsp90 inhibition, such as off-target toxicities and lack of translational efficacy.
Documented Applications
Treatment of cancer, including but not limited to carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, seminoma, and specific cancers such as those of the bladder, blood, bone, brain, breast, cervix, colon/rectum, endometrium, head and neck, kidney, liver, lung, muscle tissue, ovary, pancreas, prostate, skin, spleen, stomach, testicle, thyroid, or uterus.
Treatment of viral diseases such as hepatitis C.
Treatment of anti-inflammatory diseases including rheumatoid arthritis, asthma, MS, type I diabetes, lupus, psoriasis, and inflammatory bowel disease.
Treatment of angiogenesis-related diseases.
Prevention and treatment of chemotherapy-induced toxicity.
Treatment of protein misfolding or aggregation diseases, including scrapie/CJD, Huntington's disease, and Alzheimer's disease.
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