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Modified Experimental Conditions for Noise-Induced Hearing Loss in Mice and Assessment of Hearing Function and Outer Hair Cell Damage
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Development of Second-Generation CDK2 Inhibitors for the Prevention of Cisplatin-Induced Hearing Loss

Robert A Hazlitt, Tal Teitz, Justine D Bonga

    Journal of Medicinal Chemistry
    |August 10, 2018
    PubMed

    Insights

    New compounds AT7519 and AZD5438 show promise in preventing cisplatin-induced hearing loss. These CDK2 inhibitors offer potential therapeutic strategies for chemotherapy patients experiencing ototoxicity.

    Area of Science:

    • Ototoxicity research
    • Pharmacology
    • Cancer therapeutics

    Background:

    • Cisplatin chemotherapy can cause irreversible hearing loss (ototoxicity).
    • Currently, no FDA-approved therapies exist to prevent this side effect.
    • Cyclin-dependent kinase 2 (CDK2) has been identified as a potential therapeutic target.

    Purpose of the Study:

    • To identify novel compounds that inhibit CDK2 and prevent cisplatin-induced ototoxicity.
    • To evaluate the efficacy of identified compounds in preclinical models.

    Main Methods:

    • Screening of 187 CDK2 inhibitors in a cisplatin-treated mouse cochlear cell line.
    • Focused screening of AT7519 analogues.
    • In vivo testing of lead compounds (AZD5438 and analogue 7) in mice.

    Main Results:

    • Two lead compounds, AT7519 and AZD5438, were identified.
    • Analogue 7, derived from AT7519, demonstrated an improved therapeutic index.
    • Both analogue 7 and AZD5438 provided significant protection against cisplatin-induced ototoxicity in mice.

    Conclusions:

    • AT7519 and AZD5438 are effective in preventing cisplatin-induced ototoxicity in vivo.
    • These findings further validate CDK2 as a druggable target for mitigating chemotherapy-related hearing loss.

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