Stat3 inhibitors
Inventors
Tweardy, David J. • Xu, Xuejun • Kasembeli, Moses M.
Assignees
Baylor College of Medicine • National Institutes of Health NIH • US Department of Health and Human Services
Publication Number
US-8779001-B2
Publication Date
2014-07-15
Expiration Date
2029-06-03
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Abstract
Small molecule inhibitors of Stat3 and their derivatives are disclosed. Also described are methods to inhibit cell growth by use of Stat3 inhibitors, and the use of Stat3 inhibitors for the prevention and/or treatment of cancer. Further, inhibitors of Stat3 that also do not inhibit Stat1 are described as well as their derivatives. Methods of screening additional compounds for Stat3 inhibition activity and/or non-inhibition of Stat1 activity are also described herein.
Core Innovation
The invention relates to small molecule inhibitors of Stat3 and their derivatives, methods to inhibit cell growth by using these Stat3 inhibitors, and the use of Stat3 inhibitors for the prevention and/or treatment of cancer. It also describes inhibitors of Stat3 that do not inhibit Stat1 and their derivatives, along with methods of screening additional compounds for Stat3 inhibition activity and/or non-inhibition of Stat1 activity.
The problem addressed by the invention is that Stat3 is an oncogene constitutively active in many cancers, contributing to oncogenesis, while Stat1 is anti-oncogenic and promotes tumor surveillance. Existing drugs targeting Stat3 vs. Stat1 had empirical selectivity determined post-identification, not built into the screening process. Therefore, there is a need to provide novel compounds and methods for selectively inhibiting Stat3 without inhibiting Stat1.
The core innovation is a small-molecule virtual ligand screening approach targeting the pY-peptide binding pocket of the Stat3 SH2 domain at three sites: the pY-residue binding site, the +3 residue binding site, and a hydrophobic pocket that serves as a selectivity filter. This approach identified novel lead compounds that competitively inhibit Stat3 binding to its pY-peptide ligand, are selective for Stat3 versus Stat1, and induce apoptosis preferentially in breast cancer cell lines with constitutively activated Stat3. One compound (Cpd188) showed activity in the nanomolar range.
The invention encompasses methods and compositions useful for inhibiting Stat3 activity, inducing apoptosis in cancer cells, inhibiting angiogenesis in tumors, enhancing anti-tumor immune-mediated cytotoxicity, decreasing tumor growth, improving animal survival, inhibiting Stat3 phosphorylation and nuclear-to-cytoplasmic translocation, while sparing Stat1. The compounds interact with the Stat3 SH2 domain fulfilling defined criteria of interaction analysis and include specific chemical structures and derivatives. The invention also includes methods for identifying inhibitors selective for other STAT family members.
Claims Coverage
The patent contains multiple independent claims focusing on methods using specific chemical compounds to inhibit Stat3, with selectivity over Stat1, for treating diseases including cancer and kits comprising such compounds.
Methods of inhibiting Stat3 in cells using specified compounds
Methods comprise delivering to a cell (in vivo or in vitro) an effective amount of specific compounds that competitively inhibit Stat3 by targeting its SH2 domain, inhibiting ligand-mediated phosphorylation, and having selectivity not to inhibit Stat1.
Treatment of diseases including cancer using Stat3 inhibitors
Methods for ameliorating head and neck cancer, breast cancer, or leukemia by administering to an individual specified Stat3 inhibitor compounds, optionally in combination with additional cancer therapies such as chemotherapy, surgery, or radiation.
Selective inhibition of Stat3 without inhibiting Stat1
Stat3 inhibitors act selectively to inhibit Stat3 activity without inhibiting Stat1, preserving Stat1’s anti-oncogenic functions, including compounds that inhibit Stat3 phosphorylation and nuclear translocation while sparing Stat1 activation.
Use of Stat3 inhibitors to target cancer stem cells
Stat3 inhibitors effectively inhibit Stat3 in cancer stem cells such as leukemic stem cells or breast cancer stem cells, contributing to cancer treatment at a stem cell level.
Kits for cancer treatment comprising Stat3 inhibitors
Kits comprise the specified Stat3 inhibitor compounds contained in appropriate containers, optionally including additional cancer treatment agents for combined therapeutic use.
The claims collectively cover methods of using specified small molecule compounds as selective inhibitors of Stat3, with selectivity over Stat1, to inhibit Stat3 activity in cells including cancer stem cells, methods of treating various cancers and diseases with these compounds, and kits comprising these compounds for cancer treatment.
Stated Advantages
The compounds selectively inhibit Stat3 while sparing Stat1, potentially providing a synergistic anti-tumor effect by leaving Stat1’s anti-oncogenic functions intact.
The virtual ligand screening approach enables identification of compounds that competitively inhibit Stat3 binding to its pY-peptide ligand with high selectivity and potency, including nanomolar activity.
These inhibitors induce apoptosis preferentially in cancer cells with constitutively active Stat3, including breast cancer cell lines and leukemia stem cells.
Selective targeting of Stat3 provides broader utility in cancer treatment because Stat3 acts as a convergence point for multiple oncogenic kinases.
The invention facilitates development of chemical probes to study Stat3 function and potentially that of other STAT family members.
Documented Applications
Use of Stat3 inhibitors for the prevention and/or treatment of various cancers including breast, prostate, lung, colon, multiple myeloma, and leukemia.
Selective inhibition of Stat3 in cancer stem cells such as leukemic stem cells and breast cancer stem cells to improve cancer treatment efficacy.
Treatment of hyperproliferative diseases including post-transplant lymphoproliferative disease and restenosis.
Treatment of chronic viral infections such as hepatitis C and Epstein-Barr virus infection.
Treatment of pulmonary fibrosis, myelofibrosis, myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), asthma, psoriasis, inflammatory bowel disease, uveitis, scleritis, multiple sclerosis, graft-versus-host diseases, pancreatitis, pulmonary lymphangioleiomyomatosis, age-related macular degeneration, and amyloidosis.
Use in combination therapy along with chemotherapy, surgery, radiation, immunotherapy, gene therapy, and other cancer treatment modalities.
Screening methods for identifying inhibitors of Stat3 and other members of the STAT protein family.
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