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Discovery of a bifunctional PKMYT1-targeting PROTAC empowered by AI-generation
Yazhou Wang1, Xiaomin Wang1, Tingting Liu1
1Insilico Medicine Shanghai Ltd., Shanghai, China.
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.
Insights
A novel bifunctional PKMYT1 degrader, D16-M1P2, shows potent and selective dual inhibition and degradation of PKMYT1 (Protein Kinase MYT1). This PROTAC demonstrates significant antitumor activity and oral bioavailability, offering a promising new avenue for cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Protein Kinase MYT1 (PKMYT1) is a therapeutic target in precision cancer therapy, particularly for cancers with CCNE1 amplification or FBXW7/PPP2R1A mutations.
- Existing small molecule PKMYT1 inhibitors have limitations in molecular diversity and selectivity.
Purpose of the Study:
- To develop a novel bifunctional PKMYT1 degrader using a generative AI platform.
- To create a PROTAC (proteolysis-targeting chimera) with a new PKMYT1 inhibitor and an optimized cereblon (CRBN) binder.
Main Methods:
- Utilized a generative AI platform to design a novel PKMYT1 inhibitor.
- Linked the inhibitor to an optimized CRBN binder to create a bifunctional PROTAC, D16-M1P2.
- Evaluated the PROTAC's antiproliferative potency, selectivity, oral bioavailability, pharmacodynamic effects, and in vivo antitumor response.
Main Results:
- The lead PROTAC, D16-M1P2, exhibits dual mechanisms of PKMYT1 degradation and inhibition.
- D16-M1P2 demonstrates strong antiproliferative potency with high selectivity.
- The PROTAC shows favorable oral bioavailability, enhanced pharmacodynamic effects compared to the inhibitor alone, and robust monotherapy antitumor response in xenograft models.
Conclusions:
- D16-M1P2 represents a promising lead compound for cancer therapy, offering dual PKMYT1 degradation and inhibition.
- This PROTAC serves as a valuable chemical probe for studying PKMYT1 biology.
- The findings support further exploration of this PROTAC for advanced cancer treatment strategies.
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