2. Academic Validation
  3. Discovery of a bifunctional PKMYT1-targeting PROTAC empowered by AI-generation

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

  • Nat Commun. 2025 Nov 28;16(1):10759. doi: 10.1038/s41467-025-65796-8.
Yazhou Wang # 1,  Xiaomin Wang # 1,  Tingting Liu # 1,  Chao Wang 1,  Qingshuo Meng 1,  Fanye Meng 1,  Jiaojiao Yu 1,  Jinxin Liu 1,  Yaya Fan 1,  David Gennert 2,  Frank W Pun 3,  Alex Aliper 4,  Feng Ren 1 3,  Man Zhang 1,  Xin Cai 5,  Xiao Ding 6 7 8,  Alex Zhavoronkov 9 10 11 12
Affiliations

Affiliations

  • 1 Insilico Medicine Shanghai Ltd., Shanghai, China.
  • 2 Insilico Medicine US Inc., Cambridge, MA, USA.
  • 3 Insilico Medicine Hong Kong Ltd., Hong Kong SAR, China.
  • 4 Insilico Medicine AI Ltd., Masdar City, Abu Dhabi, UAE.
  • 5 Insilico Medicine Shanghai Ltd., Shanghai, China. [email protected].
  • 6 Insilico Medicine Shanghai Ltd., Shanghai, China. [email protected].
  • 7 Insilico Medicine US Inc., Cambridge, MA, USA. [email protected].
  • 8 Insilico Medicine AI Ltd., Masdar City, Abu Dhabi, UAE. [email protected].
  • 9 Insilico Medicine Shanghai Ltd., Shanghai, China. [email protected].
  • 10 Insilico Medicine US Inc., Cambridge, MA, USA. [email protected].
  • 11 Insilico Medicine Hong Kong Ltd., Hong Kong SAR, China. [email protected].
  • 12 Insilico Medicine AI Ltd., Masdar City, Abu Dhabi, UAE. [email protected].
  • # Contributed equally.
PMID: 41315240 DOI: 10.1038/s41467-025-65796-8
Abstract

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.

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