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Innovative Inhibitors of Creatine Kinase Pathway Metabolism Offer New Hope for Colon Cancer Therapy 

  • Therapeutics
  • 2024

Colorectal cancer remains a formidable challenge, particularly in its metastatic form, which is often resistant to current treatments. Addressing this critical need, a groundbreaking research project led by Edward Chouchani, PhD, Associate Professor of the Department of Cancer Biology Program at Dana-Farber, explores innovative approaches to target cancer metabolism. This project, newly funded by the Dana-Farber Accelerator, targets the metabolic dependencies of cancer cells on creatine energetics, particularly the creatine kinase pathway, which plays a crucial role in cellular energy management.  

An Already De-Risked Pathway 

Cancer cells, particularly those in aggressive forms like metastatic colorectal cancer, have been shown to depend heavily on creatine metabolism. This pathway involves the conversion of creatine into creatine phosphate, an energy reserve that supports rapid cell proliferation. 

“In the last eight years or so, a lot of preclinical and clinical findings have shown that creatine metabolism appears to be an important dependency for this type of cancer,” Chouchani says, whose lab has long studied this pathway. But historically, researchers have been a bit hesitant to attempt to manipulate metabolism pathways like creatine simply because it is needed for normal bodily function. 

But Chouchani believes this strategy of but Chouchani believes this strategy of already been de-risked. For decades, scientists have used the molecule β-Guanidinopropionic acid (β -GPA) successfully to poison the creatine pathway yet it is extremely well-tolerated by mice and early clinical work shows preliminary efficacy in humans for colorectal cancer. However, the already been de-risked. For decades, scientists have used the molecule β-Guanidinopropionic acid (β -GPA) successfully to poison the creatine pathway yet it is extremely well-tolerated by mice and early clinical work shows preliminary efficacy in humans for colorectal cancer. However, the require extremely high dosing. 

If successful, this could lead to a new class of therapeutics that are not only more effective but also better tolerated by patients,

Ed Chouchani

Encouraged by these findings, Chouchani’s team set out to develop next-generation creatine inhibitors with nanomolar potency to disrupt the cancer cells’ energy supply. “We wanted to make a more efficacious therapy for colorectal cancer targeting creatine energetics, especially considering how the pathway has been de-risked,” Chouchani adds. 

The Chouchani team recognized that the creatine kinase has an active site cysteine residue that is critical for activity. Using a platform in their lab to screen small molecules as covalent ligands for cysteines, they identified a covalent inhibitor. Their discovery was published in a 2023 Nature Chemical Biology 1 paper as a first-in-class creatine kinase inhibitor. However, the pharmacokinetics were poor. 

Moving forward with Dana-Farber Accelerator funding, Chouchani plans on screening, identifying, and synthesizing drug-like molecules that target the same cysteine residue. To date, the team has identified a series of molecules that are much more stable and potent in animal studies than the first-generation compound. 

“We are ready now to scale up the synthesis of lead molecules and ultimately put them head-to-head with the current standard of care for treating metastatic colorectal cancer in mouse models,” says Chouchani. The potential benefits of this technology are significant. By selectively targeting cancer cells’ metabolic pathways, this treatment could offer a more precise and less toxic alternative to traditional chemotherapy. “If successful, this could lead to a new class of therapeutics that are not only more effective but also better tolerated by patients, improving their quality of life during treatment,” Chouchani Emphasizes. 

Collaborations with other scientists have been instrumental in advancing this research, notably with Profs. Nathanael Gray and Tinghu Zhang at Stanford University, and Prof. Jianwei (John) Che of the Computational Chemistry Core at Pat Dana-Farber. Lorem ipsum dolor sit amet consectetur. Scelerisque mauris ultrices scelerisque in non. Lobortis adipiscing molestie blandit non. Curabitur massa diam nullam turpis eu a volutpat egestas nulla. Odio et semper condimentum risus porttitor at eget dolor ultrices. Lectus enim phasellus ipsum est rhoncus. Eget ac massa nascetur eget maecenas urna sem posuere pellentesque. Consectetur faucibus at non lectus nascetur. Consectetur massa sit scelerisque sagittis diam. Facilisis vel eget malesuada iaculis mollis adipiscing. Eu lacus neque dignissim faucibus feugiat ultrices. Vitae gravida condimentum justo quisque adipiscing scelerisque. Mi et gravida Priscilla ornare Ohio blandit. Commodo venenatis ut turpis consequat tempus. Eget libero vitae ipsum in ac adipiscing dolor.

Team Members: Edward Chouchani, PhD, Nathanael Gray, PhD, Tinghu Zhang, PhD, Jianwei Che, PhD, Emma Fink, MD, PhD

Team Members