TRPV2 antagonists
This invention relates to the finding that Piperlongumine compounds, such as Piperlongumine and analogues, derivatives and prodrugs thereof, are reversible, allosteric antagonists of transient receptor potential vanilloid 2 channel (TRPV2). Methods of treatment of conditions that are characterised by TRPV2 expression using Piperlongumine compounds and Piperlongumine compounds for use in such treatments are provided.
1. A method of selecting a cancer patient for treatment with a piperlongumine compound comprising
providing a sample of cancer cells from a cancer patient,
determining the presence of TRPV2 expression in the cancer cells, and
selecting a cancer patient with cancer cells that express TRPV2 for treatment with the piperlongumine compound.
2. A method of treating glioblastoma in a patient comprising, intracranially administering a piperlongumine compound to the patient during resection.
3. The method of claim 2 , wherein the piperlongumine compound is a reversible antagonist of TRPV2.
4. The method of claim 3 , wherein the piperlongumine compound has the formula 1:
wherein Q 1 is O or S,
—Ar is an optionally substituted aryl group,
-D- is selected from —C(O)—, —C(S)—, —CH(OH)— and —CH(SH)—, and —R 1 and —R 2 , together with —N-D- to which they are attached, form an optionally substituted heterocyclic ring, or —R 1 and —R 2 are each independently selected from hydrogen and optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and aryl,
and salts, solvates and protected forms thereof.
5. The method of claim 2 , wherein the piperlongumine compound is piperlongumine, or a salt, ester, or prodrug thereof.
6. The method of claim 2 , wherein the glioblastoma is primary glioblastoma.
7. The method of claim 2 , wherein the glioblastoma is recurrent glioblastoma.
8. The method of claim 2 , wherein the piperlongumine compound is encapsulated in a hydrogel for post-surgical implant.
9. The method of claim 8 , wherein the hydrogel provides a release of the piperlongumine compound for at least 192 hours.
10. The method of claim 8 , wherein the hydrogel provides a substantial release of the piperlongumine compound over the first four hours.
11. The method of claim 8 , wherein the hydrogel is decorated with aldehyde groups.
12. The method of claim 2 , wherein the piperlongumine compound is administered in a range of about 100 μg to about 400 mg.
13. The method of claim 8 , wherein the piperlongumine compound is encapsulated in a cyclodextrin, which is optionally 2-hydroxypropyl-P-cyclodextrin.
14. The method of claim 8 , wherein the hydrogel is a dendrimer-dextran hydrogel.