Issue Date: April 9, 2012
Covalent Ties Reversed
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
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