Targeted covalent probes and inhibitors of proteins containing redox-sensitive cysteines
Covalent, irreversible small-molecule inhibitors that modify the sulfenyl form (i.e., sulfenic acid, RSOH and sulfenamide, RSNR′2) of therapeutically important proteins (particularly kinases and phosphatases) are disclosed, where the compositions include a compound having a substituted aryl or heterocyclic core structure that promotes binding interactions with a specific protein, and a nucleophilic reaction center (carbon, nitrogen, sulfur, or phosphorous) that is capable of forming a covalent bond with a sulfenic acid- or sulfenamide-modified cysteine residue in the protein. Methods for synthesizing these compounds are also disclosed, as well as methods of using them for determining the bioactivity of a chemical composition comprising an active compound toward a specific protein and for determining the potency of an inhibitor against a specific protein.
1. A compound for modifying the activity of a protein phosphatase, wherein the protein phosphatase comprises a redox-sensitive cysteine, the compound comprising a nucleophilic warhead wherein the warhead can form a covalent bond with a sulfenic acid-modified or sulfenamide-modified form of the redox-sensitive cysteine; and a binding module;
wherein the compound is of one of the following formulas:
Formula TDZ-11:
Formula IX:
wherein:
A is a carbonyl group or a sulfonyl group;
Q is a carbon atom or a nitrogen atom;
R 1 is a hydrogen atom or any straight, branched, or cyclic alkyl functional group; and
R 2 is a hydrogen atom or any straight, branched or cyclic alkyl functional group;
or,
Formula XI:
wherein:
A is a carbonyl group or a sulfonyl group;
Q is a carbon atom or a nitrogen atom;
a is a single bond or a double bond; and
n is 0 or 1.
2. A method of modifying the activity of a protein phosphatase, comprising:
exposing the protein to a compound of claim 1 .
3. A method of treating diabetes in a subject, comprising:
administering to a subject afflicted with a disease, a therapeutically effective amount of a compound, wherein the compound is any one of the compounds of claim 1 .
4. The compound of claim 1 , wherein for the compound of formula (IX), A is a sulfonyl group.
5. The compound of claim 1 , wherein for the compound of formula (IX), Q is a nitrogen atom.
6. The compound of claim 1 , wherein for the compound of formula (XI), Q is a carbon atom.
7. The compound of claim 1 , wherein for the compound of formula (XI), a is a double bond.
8. The compound of claim 1 , wherein for the compound of formula (XI), A is a sulfonyl group.
9. The method of claim 2 , wherein the phosphatase is PTP1B.