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Discovery of HyT-based degraders of CDK9-Cyclin T1 complex
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  • Rongkun Lin,
  • Jie Yang,
  • Ting Liu,
  • Mingyu Wang,
  • Chongrong Ke,
  • Cheng Luo,
  • jin lin,
  • Jiacheng Li,
  • Hua Lin
Rongkun Lin
Fujian Medical University
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Jie Yang
Fujian Normal University
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Ting Liu
Fujian Medical University
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Mingyu Wang
Chinese Academy of Sciences
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Chongrong Ke
Fujian Normal University
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Cheng Luo
Chinese Academy of Sciences
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jin lin
Fujian Medical University
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Jiacheng Li
Chinese Academy of Sciences
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Hua Lin
Fujian Normal University

Corresponding Author:[email protected]

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Abstract

Targeted protein degradation technology can achieve the modulation of undruggable proteins. Abnormal activation of cyclins can promote tumorigenesis and tumor progression. However, cyclins regard to be undruggable with no small-molecule binders had been released. Here, we utilize hydrophobic tag (HyT)-based small-molecule degraders induced degradation of cyclin T1 and its corresponding kinase partner CDK9. We describe the discovery of a series of novel dual degraders of CDK9-cyclin T1. LL-CDK9-12 demonstrated the most potent and selective degradation ability, with DC50 values of 0.362 μM against CDK9 and 0.680 μM against cyclin T1. In prostate cancer cells, LL-CDK9-12 showed enhanced anti-proliferative activity than its parental molecule SNS032. Moreover, LL-CDK9-12 suppressed the downstream signaling of CDK9 and AR efficiently. Altogether, LL-CDK9-12 was an effective dual degrader of CDK9-cyclin T1 and could be useful in studying the unknown function of CDK9-cyclin T1. Our data also suggest that HyT-based degraders could be used as a strategy to induce the degradation of protein complexes that containing undruggable proteins such as cyclins.