CDK9 targeting PROTAC L055 inhibits ERα-positive breast cancer - 23/07/24

Doi : 10.1016/j.biopha.2024.116972

Wenmin Chen ^a,^b,^g,^{^{1
These authors contribute equally.}}, Yue Wu ^c,^{^{1
These authors contribute equally.}}, Chuanyu Yang ^a,^{^{1
These authors contribute equally.}}, Wenlong Ren ^a,ⁱ, Lei Hou ^j, Huichun Liang ^a, Tingyue Wu ^a,ⁱ, Yanjie Kong ^h,^⁎ , Jiao Wu ^f,^⁎ , Yu Rao ^c,^⁎ , Ceshi Chen ^a,^d,^e,^⁎
^a Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China
^b Kunming College of Life Sciences, University of Chinese Academy Sciences, Kunming 650204, China
^c MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing 100084, China
^d Academy of Biomedical Engineering, Kunming Medical University, Kunming 650500, China
^e The Third Affiliated Hospital, Kunming Medical University, Kunming 650118, China
^f Department of the Second Medical Oncology, The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, China
^g Department of Basic Medical Sciences, Beihai Vocational College of Wellness, Beihai 536000, China
^h Pathology Department, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518035, China
ⁱ School of Life Science, University of Science & Technology of China, Hefei, Anhui 230027, China
^j Department of Breast Disease, Henan Breast Cancer Center, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China

^⁎Corresponding author at: Academy of Biomedical Engineering, Kunming Medical University, Kunming 650500, China.Academy of Biomedical Engineering, Kunming Medical UniversityKunming650500China^⁎⁎Corresponding authors.

Abstract

Breast cancer is one of the most prevalent malignancies affecting women worldwide, underscoring the urgent need for more effective and specific treatments. Proteolysis-targeting chimeras (PROTACs) have emerged as a promising strategy to develop new lead compounds by selectively targeting oncoproteins for degradation. In this study, we designed, synthesized and evaluated a CRBN-based PROTAC, L055, which targets CDK9. Our findings demonstrate that L055 effectively inhibits the proliferation, induces cell cycle arrest, and decreases the survival of ERα-positive breast cancer cells in vitro. L055 specifically binds to CDK9, facilitating its degradation via the CRBN-dependent proteasomal pathway. Additionally, L055 suppressed the growth of organoids and tumors derived from T47D and MCF7 cells in nude mice. Thus, L055 represents a potential novel therapeutic agent for ERα-positive breast cancer and potentially other malignancies.

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Graphical Abstract

CRBN-based PROTAC L055 inhibits ERα-positive breast cancer partially through degrade CDK9 and decrease downstream target genes’ expression.

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Highlights

•	CRBN-based PROTAC, L055 inhibits the proliferation, induces cell cycle arrest, and decreases the survival of ERα-positive breast cancer cells.
•	L055 suppressed the growth of organoids and tumors.
•	L055 binds to CDK9, facilitates CDK9 degradation via the CRBN-dependent proteasomal pathway.
•	L055 represents a potential novel therapeutic agent for ERα-positive breast cancer.

Le texte complet de cet article est disponible en PDF.

Keywords : ERα-positive breast cancer, Proteolysis-targeting chimeras, Cyclin dependent kinase 9, CRBN

Plan

Introduction

Result

L055 inhibits the growth of ERα-positive breast cancer cells

L055 significantly inhibits proliferation, cell cycle progression, and colony formation and induces apoptosis in ERα-positive breast cancer cells in vitro

L055 inhibits breast cancer organoids and tumor growth

L055 specifically targets CDK9 for degradation and functions through CDK9

L055 promotes CDK9 proteasomal degradation depending on the CRBN E3 ubiquitin ligase

Discussion

Materials and methods

Reagents and plasmids

Compound library and L055

Cell culture

Cell viability and proliferation assays

Colony formation assay

Cell cycle and apoptosis analysis

Western blot

Cell transfection

Proteomics

TCGA database information

Tumorigenesis

Immunohistochemistry

Surface plasmon resonance (SPR) assays

Construction of a breast cancer organoid model

Kinase competitive binding assays

Statistical analysis

Funding

CRediT authorship contribution statement

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Vol 177

Article 116972- août 2024 Retour au numéro

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CDK9 targeting PROTAC L055 inhibits ERα-positive breast cancer - 23/07/24

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