Membrane Ubiquitin ligases to target protein degradation
AssigneeUMC Utrecht Holding B.V.
InventorMadelon Maria Maurice
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Abstract
The invention pertains to a heterobifunctional molecule comprising a first and a second binding domain, wherein i) the first binding domain is capable of specific binding to a transmembrane E3 ubiquitin ligase; and ii) the second binding domain is capable of specific binding to a transmembrane protein, wherein simultaneous binding of the heterobifunctional molecule to the transmembrane E3 ubiquitin ligase and the transmembrane protein results in ubiquitination and internalisation of the transmembrane protein. The invention further pertains to the heterobifunctional molecule for use in the treatment of a disease, wherein preferably the disease is at least one of cancer, an auto-immune disease, an inflammatory disease, an infectious disease and a hereditary disease.
Claims22
A heterobifunctional molecule comprising a first and a second binding domain, wherein
- i) the first binding domain is capable of specific binding to a transmembrane E3 ubiquitin ligase;
- and
- ii) the second binding domain is capable of specific binding to a transmembrane protein, wherein simultaneous binding of the heterobifunctional molecule to the transmembrane E3 ubiquitin ligase and the transmembrane protein preferably results in ubiquitination and internalisation of the transmembrane protein.
-17. (canceled)
-20. (canceled)
A method for decreasing the surface level of a membrane-bound protein of a cell, wherein the method comprises the steps of
- a) Providing a cell expressing a transmembrane E3 ubiquitin ligase and the membrane-bound protein at its cell surface;
- b) Exposing the cell to a heterobifunctional molecule, wherein the heterobifunctional molecule comprises:
- i) a first binding domain capable of specific binding to an extracellular portion of the transmembrane E3 ubiquitin ligase;
- and
- ii) a second binding domain capable of specific binding to an extracellular portion of the membrane-bound protein;
- and
- c) optionally determining the surface levels of the membrane-bound protein of the cell,
- wherein the decrease is a decrease as compared to the surface levels of the membrane-bound protein of the cell prior to step b).
The method according to claim 24, wherein the subject suffers from a cancer selected from the group consisting of colorectal cancer, ovarian cancer, breast cancer, oesophagal cancer, gastric cancer, prostate cancer, lung cancer, melanoma, leukemia, pancreatic cancer and bladder cancer
Dependencies are inferred from the claim text.