Hypoxia-inducible factor 1 (HIF-1) inhibitors
Inventors
Gustafson, Kirk R. • Schnermann, Martin J. • Chan, Susanna T. S. • Patel, Paresma R. • Figg, William D. • McMahon, James B.
Assignees
US Department of Health and Human Services
Publication Number
US-10246463-B2
Publication Date
2019-04-02
Expiration Date
2036-04-06
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Abstract
Embodiments of small molecule inhibitors of hypoxia inducible factor 1 (HIF-1) and pharmaceutical compositions thereof are disclosed. The disclosed compounds suppress HIF-1 activity by inhibiting the interaction between the HIF-1 α subunit and transcriptional co-activator protein p300. Embodiments of methods for making and using the small molecule inhibitors are also disclosed.
Core Innovation
The invention discloses small molecule inhibitors of hypoxia-inducible factor 1 (HIF-1), particularly compounds that suppress HIF-1 activity by inhibiting the interaction between the HIF-1 α subunit and the transcriptional co-activator protein p300. These small molecules have chemical structures defined by Formula I or II, including pharmaceutically acceptable salts thereof. Methods for making these compounds involve multi-step syntheses, and methods for using these inhibitors include contacting cells to inhibit HIF-1 activity, potentially in combination with other therapeutic agents.
The problem addressed by the invention arises from the role of HIF-1 in mediating cellular responses to hypoxia, especially in solid tumors where low oxygen conditions lead to tumor progression, metastasis, chemotherapy resistance, and poor clinical outcomes. HIF-1 is a heterodimer of α and β subunits, where the α subunit's interaction with p300 is critical for transcriptional activation under hypoxic conditions. Existing inhibitors of protein-protein interactions, like the p300/HIF-1α interaction, are rare and often show low specificity and potency.
The invention aims to provide potent and specific small molecule inhibitors that disrupt the p300/HIF-1α interaction, validated by identification of novel natural products termed eudistidines isolated from marine ascidian extracts, along with synthetic analogs having the defined chemical structures. The disclosed compounds have demonstrated inhibition of the HIF-1α-p300 interaction, blocking HIF-1 activation in cellular models, and show therapeutic potential to inhibit tumor progression, malarial infection, and inflammatory responses mediated by HIF-1.
Claims Coverage
The patent contains multiple independent claims covering compounds, pharmaceutical compositions, methods of synthesis, and methods of inhibiting HIF-1 activity using the disclosed compounds. The inventive features focus on compound structures, synthesis steps, and therapeutic uses.
Compound with chemical structures defined by Formula I and II
A compound having a chemical structure according to Formula I or II, including pharmaceutically acceptable salts, where the various substituents R1-R6, m, and n are defined with specific chemical groups and ranges to provide small molecule inhibitors of the p300/HIF-1α interaction.
Pharmaceutical compositions comprising the compounds
Pharmaceutical compositions comprising at least one compound or pharmaceutically acceptable salt thereof as defined by Formula I, optionally together with at least one pharmaceutically acceptable carrier and potentially a second therapeutic agent such as anticancer, antimalarial, or anti-inflammatory agents.
Methods of making the compounds
A multi-step method for making the compounds involving heating compound A with 1,1-dimethoxy-N,N′-dimethylmethanamine to form an intermediate, refluxing with guanidine hydrochloride to form compound B, hydrogenation with a Pd/C catalyst to form compound C, oxidation of R2—C(O)CH2X to R2—C(O)C(O)H followed by reaction with compound C to form compounds D or E, and optionally reacting compound E with a nucleophile comprising R1 to form compound F.
Method for inhibiting HIF-1 activity
A method of inhibiting hypoxia-inducible factor 1 (HIF-1) activity comprising contacting a cell with an effective amount of a compound or pharmaceutically acceptable salt thereof according to Formula I, optionally further contacting the cell with a second therapeutic agent which is an anticancer, antimalarial, or anti-inflammatory agent.
Method of administering compounds to subjects to treat conditions mediated by HIF-1
A method comprising administering to a subject a therapeutically effective amount of the disclosed compound or pharmaceutical composition for treatment of solid tumors, malaria, or inflammatory conditions mediated by HIF-1, where administration may include co-administration with a second therapeutic agent and may be given by various routes or in varied schedules.
The claims broadly cover novel compounds with defined chemical structures that inhibit the p300/HIF-1α interaction, pharmaceutical compositions including these compounds, detailed synthetic methods for preparing the compounds, and therapeutic methods using the compounds alone or with additional agents to inhibit HIF-1 activity and treat related diseases such as cancer, malaria, and inflammation.
Stated Advantages
The compounds provide specific and potent inhibition of the p300/HIF-1α protein-protein interaction, which is critical for hypoxia-induced transcriptional activation by HIF-1.
Disclosed compounds have demonstrated inhibition of HIF-1α activation in cellular models under hypoxic conditions, indicating potential efficacy in vivo.
The compounds show antimalarial activity against both chloroquine-sensitive and resistant strains of Plasmodium falciparum without cytotoxicity to mammalian cells.
The ability to combine these inhibitors with second therapeutic agents such as anticancer, antimalarial, or anti-inflammatory agents enhances their therapeutic usefulness.
Documented Applications
Treatment of solid tumors characterized by hypoxia-mediated HIF-1 activity, including colorectal, lung, renal, cervical, ovarian, hepatocellular, and prostate cancers.
Treatment or prevention of malarial infection caused by Plasmodium species, including drug-resistant strains.
Treatment of inflammatory conditions mediated by hypoxia and HIF-1 activation, such as malignant tumors, intestinal inflammation, lung inflammation, ischemia, atherosclerosis, myocardial infarction, rheumatoid arthritis, and wound healing.
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