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<p>PKMYT1 has recently emerged as a compelling therapeutic target for precision cancer therapy due to its synthetic lethality with oncogenic alterations such as <i>CCNE1</i> amplification and mutations in <i>FBXW7</i> and <i>PPP2R1A</i>. Current small molecule PKMYT1 inhibitors face limitations, such as insufficient molecular diversity and poor selectivity. We herein use our generative AI platform to develop a bifunctional PKMYT1 degrader by linking an entirely novel PKMYT1 inhibitor to an optimized cereblon (CRBN) binder. The lead PROTAC D16-M1P2 demonstrates dual mechanisms of PKMYT1 degradation and inhibition, with strong antiproliferative potency facilitated by high selectivity. It also exhibits favorable oral bioavailability, stronger pharmacodynamic effects relative to the PKMYT1 inhibitor alone, and robust antitumor response as a monotherapy in xenograft models. This PROTAC serves as a precise chemical probe to explore PKMYT1 biology and a promising lead for further cancer therapy exploration.</p>

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Discovery of a bifunctional PKMYT1-targeting PROTAC empowered by AI-generation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月28日

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  • Yazhou Wang,
  • Xiaomin Wang,
  • Tingting Liu,
  • Chao Wang,
  • Qingshuo Meng,
  • Fanye Meng,
  • Jiaojiao Yu,
  • Jinxin Liu,
  • Yaya Fan,
  • David Gennert,
  • Frank W. Pun,
  • Alex Aliper,
  • Feng Ren,
  • Man Zhang,
  • Xin Cai,
  • Xiao Ding,
  • Alex Zhavoronkov

摘要

PKMYT1 has recently emerged as a compelling therapeutic target for precision cancer therapy due to its synthetic lethality with oncogenic alterations such as CCNE1 amplification and mutations in FBXW7 and PPP2R1A. Current small molecule PKMYT1 inhibitors face limitations, such as insufficient molecular diversity and poor selectivity. We herein use our generative AI platform to develop a bifunctional PKMYT1 degrader by linking an entirely novel PKMYT1 inhibitor to an optimized cereblon (CRBN) binder. The lead PROTAC D16-M1P2 demonstrates dual mechanisms of PKMYT1 degradation and inhibition, with strong antiproliferative potency facilitated by high selectivity. It also exhibits favorable oral bioavailability, stronger pharmacodynamic effects relative to the PKMYT1 inhibitor alone, and robust antitumor response as a monotherapy in xenograft models. This PROTAC serves as a precise chemical probe to explore PKMYT1 biology and a promising lead for further cancer therapy exploration.