In silico identification of a novel Cdc2-like kinase 2 (CLK2) inhibitor in triple negative breast cancer

Sep 21, 2026

Uploaded by Eliana

Dysregulation of RNA splicing drives tumorigenesis across cancers, with Cdc2-like kinase 2 (CLK2) acting as a key RNA-splicing kinase implicated in breast cancer and especially triple-negative breast cancer (TNBC). A structure-based virtual screening strategy was used to discover novel CLK2 inhibitors, identifying compound 670551 as a selective candidate. Compound 670551 showed an IC50 of 619.7 nM and strong CLK2 selectivity over other kinases. Cell-based assays indicated reduced RNA splicing proteins (SRSF4, SRSF6), decreased TNBC survival and proliferation, and induction of apoptosis, supporting CLK2 inhibition as a promising TNBC therapeutic approach.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages11

Reading Time28 min

AccessFree to download

Abstract

Introduction

Triple-negative breast cancer and splicing dysregulation

Structure-based virtual screening strategy

DOI: 10.1002/pro.5004 RESE ARCH ARTICL E In silico identification of a novel Cdc2-like kinase 2 (CLK2) inhibitor in triple negative breast cancer Cheng-Chiao Huang 1,2,3 | Chia-Ming Hsu 3 | Min-Wu Chao 4,5,6 | Kai-Cheng Hsu 1,3,7,8,9 | Tony Eight Lin 1,3 | Shih-Chung Yen 10 | Huang-Ju Tu 3 | Shiow-Lin Pan 1,3,7,8,9 1Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan 2Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan 3Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan 4School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan 5Institute of Biopharmaceutical Sciences, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan 6The Doctoral Program of Clinical and Experimental Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan 7Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan 8TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan 9TMU Research Center of Drug Discovery, Taipei Medical University, Taipei, Taiwan 10Warshel Institute for Computational Biology, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong, China Correspondence Shiow-Lin Pan and Huang-Ju Tu, 301, Yuantong Rd., Zhonghe Dist., New Taipei City 235, Taiwan. Email: [slpan@tmu.edu.tw](slpan@tmu.edu.tw and hjt@tmu)[ and](slpan@tmu.edu.tw and hjt@tmu)[ hjt@tmu](slpan@tmu.edu.tw and hjt@tmu). [edu.tw](edu.tw) Funding information Ministry of Science and Technology, Grant/Award Number: MOST 112-2320-B- 038-052; Academia Sinica, Grant/Award Number: AS-BRPT-112-11; TMU Research Center of Cancer Translational Medicine from the Higher Education Sprout Project by the Ministry of Education Review Editor: Lynn Kamerlin. Abstract Dysregulation of RNA splicing processes is intricately linked to tumorigenesis in various cancers, especially breast cancer. Cdc2-like kinase 2 (CLK2), anoncogenic RNA-splicing kinase pivotal in breast cancer, plays a significant role, particularly in the context of triple-negative breast cancer (TNBC), a subtype marked by substantial medical challenges due to its low survival rates. In this study, we employed a structure-based virtual screening (SBVS) method to identify potential CLK2 inhibitors with novel chemical structures for treating TNBC. Compound 670551 emerged as a novel CLK2 inhibitor with a 50% inhibitory concentration (IC50) value of 619.7 nM. Importantly, Compound 670551 exhibited high selectivity for CLK2 over other protein kinases. Functionally, this compound significantly reduced the survival and proliferation of TNBC cells. Results from a cell-based assay demonstrated that this inhibitor led to a decrease in RNA splicing proteins, such as SRSF4 and SRSF6, resulting in cell apoptosis. In summary, we identified a novel CLK2 inhibitor as a promising potential treatment for TNBC therapy. | Cheng-Chiao Huang and Chia-Ming Hsu have contributed equally to this study. | | --- | | This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
© 2024 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society. | Protein Science. 2024;33:e5004 . [https://doi.org/10.1002/pro.5004](https://doi.org/10.1002/pro.5004) [wileyonlinelibrary.com/journal/pro](wileyonlinelibrary.com/journal/pro) 1 of 11 KEYWOR DS CLK2, drug discovery, kinase inhibitor, structure-based virtual screening, triple-negative breast cancer 1 | INTRODUCTION Breast cancer (BC) is the most comm

FAQs

What is the main goal of this study?

To identify a novel CLK2 inhibitor using structure-based virtual screening for treatment of triple-negative breast cancer (TNBC).

Why is CLK2 relevant to triple-negative breast cancer?

CLK2 is described as an oncogenic RNA-splicing kinase that plays an important role in breast cancer, particularly in TNBC where RNA splicing dysregulation contributes to tumor biology.

What were the key experimental findings for compound 670551?

Compound 670551 inhibited CLK2 with an IC50 of 619.7 nM, showed high selectivity over other kinases, and in cell assays reduced RNA splicing proteins (SRSF4, SRSF6) leading to reduced TNBC survival/proliferation and increased apoptosis.

Sep 21, 2026

Uploaded by Eliana