Rice’s K.C. Nicolaou sets sights on cancer-related drug discovery

World-renowned chemist focuses on synthesizing natural compounds for cancer fight

Rice chemist K.C. Nicolaou is embarking on one of the biggest challenges of his professional career.

Nicolaou, an academic titan whose work has been cited more than 50,000 times, built his reputation with basic research. His lab specializes in reproducing nature’s most complex organic molecules, but he was drawn to Houston in 2013 by the prospect of refocusing his efforts on finding new drugs to fight cancer. His move from the Scripps Research Institute and the University of California at San Diego, which was supported by a recruitment grant from the Cancer Prevention and Research Institute of Texas (CPRIT), was completed last fall.

K.C. Nicolaou

“Rice gave me this wonderful opportunity, through CPRIT, and I find myself like a kid in a toy store,” said Nicolaou, whose achievements in the field of “total synthesis” are highlighted in a cover story in the March 8 issue of the Proceedings of the Royal Society. “I now have the ability to do the things that I missed in the past because I was too busy with basic research. It’s time to use all of the technology that we have created and all of the lessons that we have learned to translate all that basic science into practical, clinical applications.”

Nicolaou, the Harry C. and Olga K. Wiess Chair of Chemistry, said his new lab at Rice’s BioScience Research Collaborative (BRC) is home to about 30 graduate students and postdoctoral researchers, most of whom followed him to Rice from Scripps and UCSD. Nicolaou’s lab is a world leader in total synthesis, an area of organic chemistry that focuses on synthesizing nature’s most intriguing and complex molecules. Total synthesis is so challenging that it can often take years to succeed at recreating a particular molecule. The work has been likened to scaling Mount Everest, but Nicolaou, who fondly refers to his past target molecules as both “beautiful” and “diabolical,” said total synthesis is more akin to war and requires resourcefulness, creativity and stamina.

“It’s like a war,” he said. “It’s like a battle. It’s so challenging. You can draw a strategy for it, but it rarely works as you planned it. You find obstacles and barricades as you move forward and you have to retreat, redesign and retry.

“Molecules have character — structure and architectural character,” he said. “For the chemist, when we look at them, they are like pieces of art. We like certain molecules more than others because of their beauty and architecture. And we like them from other perspectives too, because of their potential as medicine or for the challenge they pose to us as synthetic chemists.”

This image depicts a number of biologically active molecules found in living nature that have been replicated in the laboratory of chemist K.C. Nicolaou, who joined Rice's faculty in 2013. The background shows a photograph of Earth (public domain image created by NASA) and the universe (European Southern Observatory). CREDIT: K.C. Nicolaou/Rice University

Nicolaou’s notable breakthroughs include the first synthesis of the anticancer drug taxol — an achievement that had stymied researchers for decades — and the first synthesis of the deadly toxin calicheamicin, which was first discovered in a rock from Central Texas and later used in Mylotarg as a payload in the first targeted “antibody-drug conjugate” (ADC) for cancer chemotherapy.

The Proceedings of the Royal Society article summarizes the taxol and calicheamicin research along with several other successful projects from his group. The paper, which was prompted by Nicolaou’s election as a member of the prestigious Royal Society of London last May, also includes an overview of the major achievements in total synthesis from the field’s origins in Europe in 1828.

Nicolaou said one of the challenges that total synthesis faces is keeping up with the demand for synthesized versions of “scarce natural products,” secondary metabolites isolated from mammals, plants, microorganisms and marine creatures.

“At least half of the drugs we take today have their origins in the so-called natural products,” he said. In some cases, drugs employ compounds just as they appear in nature, but in many instances slight modifications can lead to improved therapeutic outcomes and reduced toxicity. Nicolaou said synthetic chemists have an important role to play in improving the drug development process, which, despite its great achievements in delivering miraculous cures, remains rather inefficient today; more than 90 percent of candidate drugs fail before they reach the market.

“This is unacceptable,” he said. “We should be doing a better job in molecular design.”

He said another area where synthetic organic chemists can facilitate drug design is in helping to create ADCs, hybrid compounds that aim to reduce the worst side effects of chemotherapy by delivering toxic payloads directly into cancer cells. ADCs contain two components — an antibody that targets a specific type of diseased cell and a toxic drug payload — joined together through a chemical linker.

Nicolaou’s latest research involves synthesizing natural products that can be used in the fight against cancer, but he said many of the details cannot yet be discussed due to confidentiality agreements with industrial partners.

“I can tell you generally that we are working with highly potent but scarce compounds and hormones found in the human body in small amounts,” he said. “These molecules are good guys, but they are only present in our bodies physiologically in tiny amounts. We need to synthesize them in sufficient quantities in order to investigate them thoroughly and to be able to deploy them clinically.”