CDK2 inhibitors may help prevent hearing loss

(DOI: 10.1084 / jem.20172246 )

Thanks to multi-level testing, scientists have found effective compounds that can protect against hearing loss caused by the common anti-cancer drug cisplatin. In addition, experiments on mice and rats have shown that new drugs can prevent hearing loss from loud noise.

In the 1970s, cisplatin changed the treatment of cancer. Currently, this drug is considered one of the most important drugs, according to WHO. However, then and now, the drug has serious side effects, including hearing loss, a problem that affects more than 60% of patients.

The researchers, led by Jian Zuo (Jian Zuo, St. Jude Research Hospital), developed a multi-level approach to finding compounds that protect against hearing loss due to the use of cisplatin ( J. Exp. Med. 2018, DOI: 10.1084 / jem.20172246 ). Robert Hazlitt (Robert Hazlitt, Zuo Doctoral Research Laboratory) presented the new results at a poster session on Monday in the Medical Chemistry Department at the National Meeting of the American Chemical Society in New Orleans.


Kenpaullo - a CDK2 inhibitor is able to protect mice from hearing loss caused by cisplatin and loud noise.

The group tested more than 4,000 compounds for their ability to protect cochlear cells placed in 96-well plates that were treated with cisplatin, and subsequently identified about a dozen promising candidate compounds. The kenpaullone molecule was among the most effective in protecting cisplatin snails from damage in a number of model species, including rats and mice, but also zebrafish, which have an organ that allows them to detect changes in water flow and acts in the same way as inner ear cells.

Kenpaullo inhibits the enzyme cyclin-dependent kinase 2 (CDK2), which indicates that CDK2 may be a promising target to avoid hearing loss from cisplatin. To confirm this hypothesis, the group conducted research in mice with disabled genes necessary for the production of CDK2. It turned out that mice without CDK2 are able to hear better after a course of cisplatin. Compared to control mice, loud noises did not lead to such a loss of hearing in mice with CDK2 deficiency and mice that were given kenpollon. This result can affect a large number of cases than only patients with cancer, suggests Zuo.

After confirming the target, the researchers targeted CDK2 inhibitors against cells treated with cisplatin, and found two new compounds: AT7519 and AZD5438, which showed even better protective properties than kenpaullo. AZD5438, introduced into the inner ear, demonstrated a complete protective effect on hearing loss in mice. Researchers are patenting the results and preparing for publication in scientific journals.

When researchers identified CDK2 as a promising target for protection against hearing loss caused by cisplatin, they found two compounds with even stronger protective activity.

Further plans for the group include the development of drugs suitable for oral administration. Direct injection into the inner ear has several advantages, such as the use of small doses of the drug. But since the procedure requires the help of a doctor or nurse and is a bit painful, an oral medication will be preferable for patients, especially children.

“This study opens up exciting prospects for finding molecules that can prevent hearing loss associated with cisplatin use,” says Lisa Cunningham (Lisa Cunningham, senior researcher at the National Institute for Deafness and Other Communication Disorders). From a clinical point of view, she said, the discovery of molecular drugs will give researchers a starting point for further improving the protective properties and at the same time will definitely not interfere with the action of cisplatin.

Note: in addition to cisplatin, there are several drugs that cause complete or partial hearing loss. Often try to change the drug itself, but, unfortunately, it is not always possible. Therefore, it is very interesting to see a new version of the circumvention of unpleasant side effects.