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

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 () and Alex Zhavoronkov ()
Additional contact information
Yazhou Wang: Insilico Medicine Shanghai Ltd.
Xiaomin Wang: Insilico Medicine Shanghai Ltd.
Tingting Liu: Insilico Medicine Shanghai Ltd.
Chao Wang: Insilico Medicine Shanghai Ltd.
Qingshuo Meng: Insilico Medicine Shanghai Ltd.
Fanye Meng: Insilico Medicine Shanghai Ltd.
Jiaojiao Yu: Insilico Medicine Shanghai Ltd.
Jinxin Liu: Insilico Medicine Shanghai Ltd.
Yaya Fan: Insilico Medicine Shanghai Ltd.
David Gennert: Insilico Medicine US Inc.
Frank W. Pun: Insilico Medicine Hong Kong Ltd.
Alex Aliper: Insilico Medicine AI Ltd.
Feng Ren: Insilico Medicine Shanghai Ltd.
Man Zhang: Insilico Medicine Shanghai Ltd.
Xin Cai: Insilico Medicine Shanghai Ltd.
Xiao Ding: Insilico Medicine Shanghai Ltd.
Alex Zhavoronkov: Insilico Medicine Shanghai Ltd.

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-65796-8

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