If you have an ACS member number, please enter it here so we can link this account to your membership. (optional)

ACS values your privacy. By submitting your information, you are gaining access to C&EN and subscribing to our weekly newsletter. We use the information you provide to make your reading experience better, and we will never sell your data to third party members.


Biological Chemistry

Covalent drugs target cancer protein via new linker

Inhibitors block Mcl-1 protein by reversibly binding to lysines instead of cysteines

by Ryan Cross
September 15, 2016 | A version of this story appeared in Volume 94, Issue 37

Inhibitors block Mcl-1 protein by reversibly binding to lysines instead of cysteines.
Credit: Qibin Su/AstraZeneca
A model showing one of the new inhibitors docked into Mcl-1 at a lysine residue.

In healthy cells, the protein Mcl-1 does its job by interfacing with other proteins and blocking them from triggering apoptosis, or programmed cell death. In some types of cancer cells, though, there’s an overabundance of Mcl-1, which protects the malignant cells and enables rampant tumor growth.

Researchers from AstraZeneca have now successfully “drugged” Mcl-1 by creating what they say are the first reversible covalent inhibitors of a protein-protein interaction (Nat. Chem. Biol. 2016, DOI: 10.1038/nchembio.2174).

“Mcl-1 has been difficult to target using traditional medicinal chemistry approaches,” says Gizem Akçay, lead author of the new study. When two proteins interface, there’s not always a distinct binding pocket, making such interactions tough to block with a small molecule.

Compounds that covalently bind free cysteine residues on proteins are emerging as tools for inhibiting protein-protein interactions. But cysteine residues are not always present, so Akçay and colleagues sought to expand the covalent inhibitor toolbox by targeting lysine instead.

By incorporating boronic acid carbonyl linker groups into a drug scaffold previously discovered to inhibit Mcl-1, the group created compounds that blocked Mcl-1’s protein-protein interactions and killed cancer cells in the lab. “This work will provide useful starting points for developing Mcl-1 therapeutics,” Akçay says.

The reversibility of the new inhibitors’ covalent bonds is important because it minimizes binding to off-target proteins, thus reducing potential toxic side effects.

“This should accelerate the discovery of new protein-protein interaction modulators using small molecules that otherwise would not have the required physicochemical properties to dock at the protein surface,” says Pedro M. P. Gois, a bioorganic chemist at Lisbon University who has investigated the use of boronic acids for reversible lysine modifications.


This article has been sent to the following recipient:

Chemistry matters. Join us to get the news you need.