A new platform that adds bicyclobutanes to amines could be used to create covalent drugs that have fewer side effects (Science 2026, DOI: 10.1126/science.adx7219).
Drugs that make a covalent bond to their protein target have become fashionable in recent years, but many covalent drugs and drug candidates rely on acrylamide warheads to make the critical covalent bond to a cysteine residue in the target protein. But acrylamides can also latch onto other amino acids, which can lead to off-target effects. Bicyclobutane is more selective for cysteine, so it could make for more-selective covalent drugs.
“We realized that the key to solving this problem, at least in our hands, was to use a sulfur(IV)-based reagent.”
Justin M. Lopchuk, a chemistry professor at the H. Lee Moffitt Cancer Center and Research Institute, led the research effort. Lopchuk started working on bicyclobutanes when he was a postdoctoral researcher.
“One of the things we always had in the back of our mind as we saw that those bicyclobutanes were cysteine-selective was: Can we use this for covalent inhibition? Can we really enable this in drug discovery?” Lopchuk says. The problem was that there was no general way to install the bicyclobutane at the end of a drug candidate’s synthesis without interfering with other common motifs on druglike molecules.
Lopchuk and colleagues tried to add bicyclobutanes to amines on drug precursors—the same spot where drugmakers install acrylamides—by incorporating them as components of sulfonamides or sulfonimidamides. These compounds feature sulfur(VI), but the team couldn’t find a mild and general way to add these groups to the amines.
“We realized that the key to solving this problem, at least in our hands, was to use a sulfur(IV)-based reagent, which allows the bicyclobutane to be less reactive and more amenable to late-stage functionalization,” Lopchuk says. Once the sulfur(IV) reagent is added to the amine, the chemists do either an oxidation or oxidative amination to make the sulfur(VI) compounds.
Making the mental shift to sulfur(IV) “was probably the biggest intellectual hurdle and creative hurdle that we had to overcome,” Lopchuk says. “And once we did that, things got a lot smoother.”
Vincent Lindsay, who studies the organic chemistry of strained small molecules at North Carolina State University and was not involved in the work, says in an email that “through a subsequent controlled oxidation stage, the reactivity of the warhead can be readily modulated and tailored to the desired application.” This modular approach and easy installation of the sulfur(IV) bicyclobutane motif “is crucial for its general use as a common warhead in future drug discovery endeavors,” he adds.
Lopchuk and coworkers screened model bicyclobutanes against all the nucleophilic amino acids in a buffered system and saw reactions only with cysteine. Analogous acrylamides reacted with cysteine, histidine, lysine, and serine residues.
“One of the things we like about this chemistry is when you go from acrylamides, which are these sp2 flat centers, to the sulfur sp3-rich centers, you’re making very fundamentally different molecules,” Lopchuk says. That simple change in an isolated part of the molecule has “profound benefits across the board.”
The chemists also use their approach to create bicyclobutane analogs of popular covalent anticancer drugs, including ibrutinib (Imbruvica), acalabrutinib (Calquence), and dacomitinib (Vizimpro). In a head-to-head comparison of dacomitinib with its bicyclobutane analog, the researchers found both equally effective at shrinking tumors in mice.
Lopchuk and his colleagues have founded a start-up, Thyora Therapeutics, to develop the technology.
