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Drug Discovery

Small molecules shield mice against hearing loss

Using multitiered screen, scientists find potent compounds that fend off hearing loss induced by common cancer drug cisplatin

by Tien Nguyen
March 26, 2018 | APPEARED IN VOLUME 96, ISSUE 13

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Targeting the enzyme CDK2 led scientists to AZD5438, a compound with potent protective abilities against cisplatin-induced hearing loss.

The cancer drug cisplatin, though lifesaving, comes with serious side effects. One of the most common is hearing loss, which affects more than 60% of people treated with cisplatin, and for which researchers have struggled to develop FDA-approved therapies. At the meeting, researchers led by Jian Zuo at St. Jude Children’s Research Hospital described a way to find compounds that protect against cisplatin-induced hearing loss (J. Exp. Med. 2018, DOI: 10.1084/jem.20172246). The team screened more than 4,000 compounds for their ability to protect cochlear cells that had been treated with cisplatin. Among their most potent hits was the molecule kenpaullone, which was able to protect the hearing of rodents and the auditory-like organ of zebrafish from damage. Kenpaullone inhibits an enzyme called cyclin-dependent kinase 2 (CDK2), which the researchers hypothesized may be a promising target for cisplatin-induced hearing loss. They confirmed their hunch by demonstrating that mice lacking CDK2 were better able to hold on to hearing after cisplatin treatment. The researchers then evaluated known CDK2 inhibitors against cisplatin-treated cells and ultimately found two compounds, AT7519 and AZD5438, that had even better protective properties than kenpaullone. Alan Cheng of Stanford University called the work “elegant” and said the newly identified target may hold promise for other forms of cochlear damage as well.

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