Discovery could lead to cancer drugs with fewer side effects

cancer side effects

Many anticancer drugs have serious side-effects in clinical practice. Kinesin inhibitors block kinesin motor proteins required for cancer cell division, and are promising anticancer drug candidates with minimal side-effects. However, their association with kinesin proteins remains unclear. 

Researchers from Japan have addressed this by solving the crystal structure of the complex formed by the kinesin protein CENP-E and the non-hydrolyzable ATP analogue AMPPNP, paving the way for the development of cancer therapies with lesser toxicities.

Anticancer drugs are pivotal to cancer treatment, but their toxicity may not always be limited to cancer cells, resulting in harmful side-effects. To develop anticancer therapies that have fewer adverse effects on patients, scientists are focusing on molecules that are less toxic to cells. One such group of drugs is kinesin inhibitors. 

These inhibitors prevent cancer progression by explicitly targeting kinesin motor proteins, which are required for the division of cancer cells. Centromere-associated protein E (CENP-E), a member of the kinesin motor proteins, is a promising target for inhibitor therapy, as it is essential for tumor cell replication. 

However, determining the structure of CENP-E is crucial to identify inhibitor molecules that can bind to CENP-E and stop the function. 

The binding of the energy molecule—adenosine triphosphate (ATP)—to the motor domain of CENP-E changes its structure or configuration. This also occurs when CENP-E binds to an inhibitor. So far, very few CENP-E inhibitors have been reported and none have been approved for clinical use. It is, therefore, important to acquire structural information on the CENP-E motor domain.

To this end, a research team from Tokyo University of Science (TUS) used X-ray crystallography to elucidate the crystal structure of the complex formed by the CENP-E motor domain and a kinesin inhibitor.

Potential cancer drug target

The study, led by Hideshi Yokoyama from TUS, along with co-authors Asuka Shibuya from TUS, and Naohisa Ogo, Jun-ichi Sawada, and Akira Asai from the University of Shizuoka, was published in FEBS Letters

“CENP-E selectively acts on dividing cells, making it a potential new target for anticancer drugs with fewer side-effects,” Yokoyama said.

First, the team expressed the CENP-E motor domain in bacterial cells, following which they purified and mixed it with adenylyl-imidodiphosphate (AMPPNP)—a non-hydrolyzable ATP analogue. The mix was crystallized to obtain X-ray data. Using the data, the team obtained the structure of CENP-E motor domain-AMPPNP complex.

Next, they compared the structure with that of CENP-E-bound adenosine diphosphate (CENP-E-MgADP) as well as with other previously known kinesin motor protein-AMPPNP complexes. From these comparisons, the team speculated that the helix alpha 4 in the motor domain was likely to be responsible for the loose binding of CENP-E to microtubules, i.e., cell structures that are crucial to cell division.

“Compared to the α4 helices of other kinesins, the α4 of CENP-E binds slowly and with lesser strength to microtubules as compared to other kinesins, throughout the ATP hydrolysis cycle,” Yokoyama noted.

The discovery of the crystal structure of the complex is expected to facilitate additional structure-activity relationship studies, which will bring scientists a step closer to developing anticancer drugs targeting CENP-E. 

The research team said it is optimistic about the future applications of their research and are confident that it will be possible to design drugs based on the methods employed in this study. 

“The ultimate goal is to use the preparation and crystallization methods described in our study for future drug design studies that aim at developing anticancer drugs with fewer side-effects,” Yokoyama said.

Along with less side effects, both researchers and biotech companies are working toward more focused cancer treatments. In a recent article, CEOs, CMOs and CSOs shared their insights with Labiotech with respect to what cancer treatment will look like 10 years from now.

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