Abstract
Three scientists who developed a new way to join molecules together won this year’s Nobel Prize in Chemistry. These types of bioorthogonal “click” reactions are now a mainstay of drug discovery research and increasingly used to create the next generation of cancer therapeutics and diagnostics.
A special type of precision reaction that joins molecules together quickly and efficiently has been recognized with this year's Nobel Prize in Chemistry.
This bioorthogonal click chemistry, a mainstay of drug discovery research, is increasingly being used to create the next generation of cancer therapeutics and diagnostics.
“It will fundamentally change how we treat and image cancer patients,” says Jason Lewis, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY.
Two of the winners—K. Barry Sharpless, PhD, of Scripps Research in La Jolla, CA, and Morten Meldal, PhD, of the University of Copenhagen in Denmark—laid the foundation for the field 20 years ago with simultaneous reports of a simple, reliable reaction for snapping together different molecular building blocks.
That reaction became a staple of medicinal chemistry used to create molecular scaffolds with drug-like properties and to synthesize targeted medicines such as antibody–drug conjugates (ADC). Yet, because copper ions are required to catalyze molecular coupling, the method proved toxic to living cells.
A biocompatible alternative came from Carolyn Bertozzi, PhD, of Stanford University in California. In 2004, she and her colleagues described a copper-free reaction for chemically tagging sugar adornments on glycoproteins inside human cells. Cancer biologists now routinely deploy that labeling technique to study tumor development.
The Nobel Prize in Chemistry was awarded to (from left to right) Carolyn Bertozzi, Morton Meldal, and K. Barry Sharpless.
Sharpless, Meldal, and Bertozzi will share the 10 million kronor ($900,000) prize money.
“It's so exciting,” says Peng Wu, PhD, of Scripps Research, who trained with Sharpless and Bertozzi. “People have been talking about this for years. Finally, they have won!”
Click chemistry has been key in improving ADCs, which were hamstrung by safety and efficacy limitations early on. First-generation constructs lacked manufacturing precision and were not consistently conjugated at the same amino acid residue. “Now, they're more site specifically prepared,” says Bauke Albada, PhD, of Wageningen University in the Netherlands, with bioorthogonal “handles” ensuring “full control of where you attach your molecule to the antibody.”
The technique also allows researchers to unleash powerful chemotherapy drugs and cancer-targeted radioisotopes in a tightly controlled fashion.
Consider SQ3370 (Shasqi), the first clinical-stage therapeutic that takes advantage of bioorthogonal reactions performed inside the body. Now in phase I/II testing, it's comprised of a hydrogel injected directly into a tumor and a protodrug formulation of doxorubicin, activated only after the two components “click.” This allows for site-specific targeting with minimal side effects (Chem Sci 2021;12:1259–71).
“These are highly specific chemicals that recognize each other despite the presence of billions of other biomolecules,” explains Shasqi adviser/collaborator Maksim Royzen, PhD, of the University at Albany, NY, who helped develop SQ3370. What's more, “the reaction is very fast, so you can do it at reasonable timescales.”
Researchers are also using click chemistry to improve existing radiopharmaceutical strategies. In 2019, Lewis and his colleague Brian Zeglis, PhD, of Hunter College in New York, NY, showed in mouse models that by first administering a nonradioactive antibody targeting pancreatic tumors and then following up days later with an alpha particle–bearing payload that clicks exquisitely into place, they could reduce off-target toxicity (Clin Cancer Res 2019;25:868–80).
A first-in-human trial—initially with a diagnostic tracer for imaging instead of a high-energy isotope with cancer-killing potential—is planned for next year. If it proves safe and feasible, “then we can turn it into a therapy,” Lewis says.
Few large pharmaceutical companies are advancing bioorthogonally triggered therapeutics as yet—but Asier Unciti-Broceta, PhD, of the University of Edinburgh, UK, expects that to soon change. “More people are going to look at what bioorthogonal drugs can do,” he says, “and I anticipate many companies coming now on the wave of the Nobel Prize.” –Elie Dolgin
For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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