Small-molecule hydrophobic tagging of fusion proteins and induced degradation of same
The present invention includes compounds that are useful in perturbing or disrupting the function of a transmembrane or intracellular protein, whereby binding of the compounds to the transmembrane or intracellular protein induces proteasomal degradation of the transmembrane or intracellular protein. The present invention further includes a method of inducing proteasomal degradation of a transmembrane or intracellular protein. The present invention further includes a method of identifying or validating a protein of interest as a therapeutic target for treatment of a disease state or condition.
1. A compound of formula
HYD-L R ,
wherein:
HYD is a hydrophobic group selected from the group consisting of HTL-36, HTL-39 and HTL-40:
and
L R is a linker group having a reactive moiety selected from the group consisting of:
wherein the reactive moiety is capable of forming a covalent link between the HYD group and a target protein of interest.
2. The compound of claim 1 , wherein the reactive moiety is a haloalkyl group optionally substituted with a monoether or diether group.
3. The compound of claim 1 , wherein the target protein of interest comprises at least one selected from the group consisting of a haloalkane dehalogenase, O6-alkylguanine-DNA alkyltransferase, ACP synthase, SCP synthase, and SFP synthase.
4. The compound of claim 1 , wherein the hydrophobic group has a ClogP of at least 4.0.
5. The compound of claim 1 , wherein the target protein of interest is a structural protein, receptor, enzyme, cell surface protein, a protein involved in catalytic activity, an aromatase, a motor protein, a helicase, a metabolic protein, an antioxidant protein, proteolytic protein, biosynthesis related protein, a kinase, an oxidoreductase, a transferase, a hydrolase, a lyase, an isomerase, a ligase, enzyme regulator, signal transducer, cell motility related protein, membrane fusion related protein, cell communication related protein, cell differentiation related protein, cell adhesion protein, cell death protein, protein transporter, nuclear transport protein, ion transport protein, channel transporter protein, carrier protein, a permease, secretory protein, electron transport protein, chaperone protein, nucleic acid binding protein, transcription regulator protein, extracellular organization and biogenesis protein, or translation regulator protein.
6. A method of inducing degradation of a protein of interest in a cell, the method comprising: reacting intracellularly or on the surface of the cell the expressed protein of interest with a compound comprising the compound of claim 1 , wherein the compound of claim 1 , upon reaction with the protein of interest, forms a covalent bond with the protein of interest thus yielding a hydrophobically labeled protein, which undergoes degradation.