Covalent Ties Reversed | April 9, 2012 Issue - Vol. 90 Issue 15 | Chemical & Engineering News
Volume 90 Issue 15 | p. 8 | News of The Week
Issue Date: April 9, 2012

Covalent Ties Reversed

Drug Design: Dual activation groups lead to rapidly reversible covalent kinase inhibitor
Department: Science & Technology | Collection: Life Sciences
News Channels: Biological SCENE
Keywords: kinase, inhibitors, reversible, covalent drugs
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A tert-butyl cyanoacrylate-based inhibitor forms a covalent bond with one cysteine but not another in the active site of a kinase. Interactions with a threonine residue stabilize the complex and slow down the otherwise fast reverse reaction.
Credit: Courtesy of Jack Taunton
Inhibitor in the active site of p90 RSK2 forms a covalent bond with cysteine  436 but not nearby cysteine 560. hydrogen bonds with threonine 493 stabilize the complex and add specificity.
 
A tert-butyl cyanoacrylate-based inhibitor forms a covalent bond with one cysteine but not another in the active site of a kinase. Interactions with a threonine residue stabilize the complex and slow down the otherwise fast reverse reaction.
Credit: Courtesy of Jack Taunton

Reversibly targeting noncatalytic cysteine residues could lead to covalent drug molecules with improved potency and selectivity but with less potential for off-target adducts, Jack Taunton of the University of California, San Francisco, and coworkers report (Nat. Chem. Biol., DOI: 10.1038/nchembio.925). The researchers say the strategy could lead to safer drugs.

Several acrylamide-based inhibitors that covalently bind noncatalytic cysteine residues in kinases are currently in clinical development as cancer treatments. These inhibitors have the potential to form irreversible adducts with glutathione and other off-target thiols that can raise safety concerns.

Hoping to reduce such off-target adducts, Taunton’s team made inhibitors with two electron-withdrawing groups for Michael addition reactions. Because of their dual activating groups, the new inhibitors bind to protein cysteines more quickly than do the ones currently in the clinic, which have only one activating group. But the reverse reaction is also swift, Taunton says.

“By increasing the intrinsic reactivity of the electrophile,” Taunton says, “you cross into a kinetic regime in which both the forward and reverse rate constants are intrinsically very fast.”

Despite the speed of the reverse reaction, the new inhibitors form stable complexes with their protein targets, thanks to a network of specific interactions between the inhibitor and the protein. Off-target cysteines lack such stabilizing interactions, and the speedy reverse reaction prevents permanent adducts from forming.

As a test case, Taunton and his coworkers made inhibitors for one of the domains of a kinase called RSK2. They targeted a cysteine in the enzyme’s active site. The approach should work for any “druggable” site as long as there’s a nearby cysteine, Taunton says.

“This is an exciting and potentially general approach for making reversible covalent inhibitors that possess unique pharmacology,” says Nathanael S. Gray, who develops kinase inhibitors at Dana-Farber Cancer Institute.

Kendall N. Houk, a chemistry professor at UCLA, calls the work “a beautiful example of how an understanding of kinetics and thermodynamics can lead to practical consequences in the drug design field.”

 
Chemical & Engineering News
ISSN 0009-2347
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