TRPV6 blocked by a piperazine drug

Novel Drugs That Act Like Biological Plugs May Treat Aggressive Cancers

November 27, 2020

Researchers have developed a novel class of drugs that block TRPV6, a calcium channel that plays a key role in the growth of many cancers. The study was published today in Science Advances.

TRPV6 is a channel found in gut cells that captures calcium ions from the diet. Mutations or changes in TRPV6 gene expression are linked to several cancers and other diseases including hyperparathyroidism, metabolic bone disease, chronic pancreatitis, and kidney stone formation.

Calcium is an essential mineral and a signaling ion responsible for many physiological functions. Increased expression of TRPV6 leads to abnormally high levels of intracellular calcium, which in turn drive cell proliferation in some of the most dangerous human cancers, including breast, prostate, colon, ovarian, thyroid, endometrial and blood cancer. 

“Unfortunately, previous attempts to develop small-molecule inhibitors of TRPV6 have largely been unsuccessful,” says study leader Alexander I. Sobolevsky, PhD, associate professor of biochemistry & molecular biophysics at Columbia University Vagelos College of Physicians and Surgeons. “So, we took a novel approach, inspired by the calmodulin molecule, which acts like a biological plug.”

Calmodulin is a regulatory protein that prevents calcium overload by blocking the TRPV6 channel opening when it detects excess levels of calcium inside the cell.

TRPV6 blocked by a piperazine drug
Left: Calcium ions flowing through the TRPV6 channel; right: TRPV6 blocked by a piperazine drug (Credit: Sobolevsky lab)

The team used this template to design, synthesize, and characterize a new class of small-molecule piperazine derivative drugs that bind to the same region inside the channel’s calcium-releasing ‘exit pore.’

By plugging this channel, the drugs freeze TRPV6 in a state that mimics calmodulin-induced inactivation – a physiological process that has been optimized by nature through the course of evolution.

“This novel mechanism of inhibition opens up new avenues for the design of future generation biomimetic drugs,” says Sobolevsky.

Next, the drugs will be tested for effectiveness in animal models.

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References

The paper is titled “Inactivation-mimicking block of the epithelial calcium channel TRPV6.”

Contributors from Columbia University Vagelos College of Physicians and Surgeons are Arthur Neuberger, Kirill D. Nadezhdin, and Appu K. Singh. The other contributors are Rajesh Bhardwaj (University of Bern), Sonja Lindinger (Johannes Kepler University Linz), Micael R. Cunha (University of Bern), Isabella Derler (Johannes Kepler University Linz), Gergely Gyimesi (University of Bern), Jean-Louis Reymond, Matthias A. Hediger (University of Bern), and Christoph Romanin (Johannes Kepler University Linz).

The study was supported by grants from the National Institutes of Health (R01 CA206573, R01 NS083660, and R01 NS107253), the National Science Foundation, an Irma T. Hirschl Career Scientist Award, the Simons Foundation, and NYSTAR (the Empire State Development's Division of Science, Technology and Innovation).

The authors declare no financial or other conflicts of interest.