Design, Synthesis, and Computational Insights into PKMYT1 Inhibitors for the Treatment of Breast Cancer

Yu, Jinyu; Zhang, Haoyu; Su, Chuanxu; Yuan, Shizhe; Liu, Nian; Sun, Yin; Sun, Yixiang; Gao, Zixuan; Zhao, Dongmei; Cheng, Maosheng

doi:10.3390/biomedicines13092116

This is an early access version, the complete PDF, HTML, and XML versions will be available soon.

Open AccessArticle

Design, Synthesis, and Computational Insights into PKMYT1 Inhibitors for the Treatment of Breast Cancer

by

Jinyu Yu

^†,

Haoyu Zhang

^†,

Chuanxu Su

,

Shizhe Yuan

,

Nian Liu

,

Yin Sun

,

Yixiang Sun

,

Zixuan Gao

,

Dongmei Zhao

^*

and

Maosheng Cheng

Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China

^*

Author to whom correspondence should be addressed.

^†

J.Y. and H.Z. are co-first authors and contributed equally to this work

Biomedicines 2025, 13(9), 2116; https://doi.org/10.3390/biomedicines13092116

Submission received: 20 July 2025 / Revised: 17 August 2025 / Accepted: 26 August 2025 / Published: 29 August 2025

(This article belongs to the Special Issue New Horizons in Enzyme Inhibitor Discovery: Targets, Design and Evaluation)

Download Versions Notes

Abstract

Background: Membrane-associated tyrosine-threonine protein kinase 1 (PKMYT1), which is identified as a synthetic lethal partner of CCNE1, emerged as a promising therapeutic target in oncology. Methods: A series of novel PKMYT1 inhibitors were designed by employing a pharmacophore fusion strategy. The underlying mechanisms were investigated by means of pharmacological experiments and molecular simulations. Results: Compound MY-14 demonstrated optimal kinase inhibition (IC₅₀ = 0.002 μM) and significant anti-proliferative efficacy against CCNE1-amplified cells (IC_50-HCC1569 = 1.06 μM and IC_50-OVCAR3 = 0.80 μM). Furthermore, MY-14 induced concentration-dependent apoptosis, inhibited colony formation, and effectively arrested cell-cycle progression at the S-phase through synthetic lethality. Molecular dynamics simulations, Hirshfeld surface analysis, dynamic cross-correlation matrix (DCCM), and MM/GBSA calculations elucidated the molecular mechanism underlying MY-14’s interaction with PKMYT1. Conclusions: MY-14 emerged as a promising compound for the development of a novel PKMYT1 inhibitor.

Keywords: CADD; PKMYT1 inhibitors; synthetic lethal

Share and Cite

MDPI and ACS Style

Yu, J.; Zhang, H.; Su, C.; Yuan, S.; Liu, N.; Sun, Y.; Sun, Y.; Gao, Z.; Zhao, D.; Cheng, M. Design, Synthesis, and Computational Insights into PKMYT1 Inhibitors for the Treatment of Breast Cancer. Biomedicines 2025, 13, 2116. https://doi.org/10.3390/biomedicines13092116

AMA Style

Yu J, Zhang H, Su C, Yuan S, Liu N, Sun Y, Sun Y, Gao Z, Zhao D, Cheng M. Design, Synthesis, and Computational Insights into PKMYT1 Inhibitors for the Treatment of Breast Cancer. Biomedicines. 2025; 13(9):2116. https://doi.org/10.3390/biomedicines13092116

Chicago/Turabian Style

Yu, Jinyu, Haoyu Zhang, Chuanxu Su, Shizhe Yuan, Nian Liu, Yin Sun, Yixiang Sun, Zixuan Gao, Dongmei Zhao, and Maosheng Cheng. 2025. "Design, Synthesis, and Computational Insights into PKMYT1 Inhibitors for the Treatment of Breast Cancer" Biomedicines 13, no. 9: 2116. https://doi.org/10.3390/biomedicines13092116

APA Style

Yu, J., Zhang, H., Su, C., Yuan, S., Liu, N., Sun, Y., Sun, Y., Gao, Z., Zhao, D., & Cheng, M. (2025). Design, Synthesis, and Computational Insights into PKMYT1 Inhibitors for the Treatment of Breast Cancer. Biomedicines, 13(9), 2116. https://doi.org/10.3390/biomedicines13092116

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Menu

Design, Synthesis, and Computational Insights into PKMYT1 Inhibitors for the Treatment of Breast Cancer

Abstract

Share and Cite

Article Metrics

Article Access Statistics

Further Information

Guidelines

MDPI Initiatives

Follow MDPI