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<p>Cyclin-dependent kinase (CDK) 9 plays a role in the transcription elongation of HIV-1 promoter. Functional inactivation of CDK9 could attenuate HIV-1 replication. However, high homology of CDK family members poses significant challenges in developing CDK9-specific inhibitors, as promiscuous inhibition often leads to off-target toxicities. In this work, a series of novel heterobifunctional compounds was designed and synthesized by conjugating a multitargeted CDK inhibitor with the ligand of different E3 ligases via a chemical linker. A VHL-recruiting heterobifunctional compound (<b>9g</b>) was identified as a highly selective PROTAC degrader of CDK9 by both western blotting and MS-based proteomics analyses. This novel PROTAC compound effectively reduced HIV-1 RNA synthesis by blocking CDK9-mediated transcription elongation. Furthermore, it exhibited significantly lower cytotoxicity and higher anti-HIV-1 therapeutic index than its CDK9 binding warhead. In conclusion, the identification of a selective CDK9-targeted degrader provides a novel anti-HIV-1 lead and highlights the potential of the PROTAC approach for developing host-directed, broad-spectrum antiviral agent candidates.</p>

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A potent and selective PROTAC degrader of CDK9 as effective inhibitor of HIV-1 RNA synthesis

  • 期刊论文

  • 发表日期：

    2025年11月12日

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  • Bo Yang,
  • Ling Ma,
  • Xiaotang Yang,
  • Jiajia Wen,
  • Weiyi Yin,
  • Siqi Li,
  • Yingjie Ji,
  • Ying Wang,
  • Shan Cen,
  • Yanping Li

摘要

Cyclin-dependent kinase (CDK) 9 plays a role in the transcription elongation of HIV-1 promoter. Functional inactivation of CDK9 could attenuate HIV-1 replication. However, high homology of CDK family members poses significant challenges in developing CDK9-specific inhibitors, as promiscuous inhibition often leads to off-target toxicities. In this work, a series of novel heterobifunctional compounds was designed and synthesized by conjugating a multitargeted CDK inhibitor with the ligand of different E3 ligases via a chemical linker. A VHL-recruiting heterobifunctional compound (9g) was identified as a highly selective PROTAC degrader of CDK9 by both western blotting and MS-based proteomics analyses. This novel PROTAC compound effectively reduced HIV-1 RNA synthesis by blocking CDK9-mediated transcription elongation. Furthermore, it exhibited significantly lower cytotoxicity and higher anti-HIV-1 therapeutic index than its CDK9 binding warhead. In conclusion, the identification of a selective CDK9-targeted degrader provides a novel anti-HIV-1 lead and highlights the potential of the PROTAC approach for developing host-directed, broad-spectrum antiviral agent candidates.