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US 2022/0089589 A1Published application
SMALL MOLECULE DEGRADERS OF FKBP12 VIA RECRUITMENT OF VON HIPPEL-LINDAU E3 UBIQUITIN LIGASE (VHL) E3 UBIQUITIN LIGASE, AND USES IN dTAG SYSTEMS
AssigneeDana-Farber Cancer Institute, Inc.
InventorsNathanael S. Gray, Fleur M. Ferguson, Behnam Nabet, Dennis L. Buckley
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Abstract
Disclosed is a dTAG system comprising a small molecule degraders of FKBP12-tagged proteins via recruitment of Von Hippel-Lindau E3 ubiquitin ligase (VHL) E3 ubiquitin ligase and uses thereof.
Claims24
A bifunctional compound having a structure represented by formula I:
- wherein the targeting ligand represents a moiety that selectively binds a FK506-binding protein 12 (FKBP12)(F36V)-tagged protein, the degron represents a ligand that selectively binds a Von Hippel-Lindau E3 ubiquitin ligase (VHL), and the linker represents a moiety that connects covalently the degron and the targeting ligand, or a pharmaceutically acceptable salt or stereoisomer thereof.
(canceled)
-16. (canceled)
A nucleic acid which encodes a chimeric antigen receptor (CAR) protein, comprising, from N-terminus to C-terminus:
- a) an extracellular ligand binding domain that binds a tumor associated antigen;
- b) a transmembrane domain;
- c) a cytoplasmic domain comprising at least one intracellular signaling domain;
- and
- d) a dTAG FKBP12(F36V) of any one of SEQ ID NOs:
- 1-4 which is disposed at the N-terminus or between the extracellular binding domain and the transmembrane domain, provided that there is no disruption to antigen binding or insertion into the membrane;
- or at the C-terminus, between the transmembrane domain and the intracellular domain or between signaling domains when more than one is present, provided that there is no disruption to intracellular signaling or insertion into the membrane.
4 more elements
Dependencies are inferred from the claim text.