A CARM1 Inhibitor Potently Suppresses Breast Cancer Both In Vitro and In Vivo

Sep 21, 2026

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CARM1 is a PRMT family enzyme tied to cancer progression and is considered a promising target for diagnosis and therapy, yet potent and selective CARM1 inhibitors remain scarce. The study identifies iCARM1, which shows improved specificity and activity versus EZM2302 and TP-064. iCARM1 suppresses oncogenic estrogen/ERα-target gene expression, activates type I interferon signaling and ISGs, and potently inhibits breast cancer growth both in vitro and in vivo, including synergistic tumor growth suppression with endocrine drugs or etoposide.

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Abstract

Introduction

This article is licensed under CC-BY-NC-ND 4.0 [pubs.acs.org/jmc](pubs.acs.org/jmc) Article A CARM1 Inhibitor Potently Suppresses Breast Cancer Both In Vitro and In Vivo Bing-ling Peng, Ting Ran, Xue Chen, Jian-cheng Ding, Zi-rui Wang, Wen-juan Li, and Wen Liu* Cite This: J. Med. Chem. 2024, 67, 7921−7934 Read Online | | | | | | | | --- | --- | --- | --- | --- | --- | | ACCESS | Metrics & More | | Article Recommendations | | *sı Supporting Information | ABSTRACT: CARM1, belonging to the protein arginine methyltransferase (PRMT) family, is intricately associated with the progression of cancer and is viewed as a promising target for both cancer diagnosis and therapy. However, the number of specific and potent CARM1 inhibitors is limited. We herein discovered a CARM1 inhibitor, iCARM1, that showed better specificity and activity toward CARM1 compared to the known CARM1 inhibitors, EZM2302 and TP-064. Similar to CARM1 knockdown, iCARM1 suppressed the expression of oncogenic estrogen/ERα-target genes, whereas activated type I interferon (IFN) and IFN-induced genes (ISGs) in breast cancer cells. Consequently, iCARM1 potently suppressed breast cancer cell growth both in vitro and in vivo. The combination of iCARM1 with either endocrine therapy drugs or etoposide demonstrated synergistic effects in inhibiting the growth of breast tumors. In summary, targeting CARM1 by iCARM1 effectively suppresses breast tumor growth, offering a promising therapeutic approach for managing breast cancers in clinical settings. ■ INTRODUCTION Breast cancer ranks as the most prevalent form of cancer and stands as the primary cause of cancer-related fatalities among women.1 Breast cancer is traditionally categorized into five subtypes: luminal A, luminal B, HER2-positive, triple-negative, and normal-like. This classification is determined by the presence or absence of three key receptors: human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR). Luminal A and B subgroups are both ER-positive, and luminal A is PR positive but negative for HER2, while luminal B is PR negative but positive for HER2.2,3 Nearly 70% of diagnosed breast cancer patients are ER-positive, and endocrine therapy is the main means of treatment in the clinic for this subtype of breast cancer. However, primary and acquired endocrine therapy drug resistance is found in a fraction of patients. Endocrine therapy resistance commonly arises from the ligand-independent reactivation of the estrogen receptor (ER), serving as a primary driving force.4 Therefore, one of the most effective means to overcome resistance is the inhibition of ER itself or ER signaling pathway.4 As a result, effective strategies to combat drug resistance in ER-positive breast cancer therapy may involve targeting pivotal regulators within the estrogen signaling pathway. As triple-negative breast cancer (TNBC) lacks expression of ER, PR, and HER2, traditional endocrine therapy and HER2-targeted therapy are often ineffective in their treatment. Thus, alternative therapeutic approaches are required. Due to the lack of ER, PR, and HER2 receptors, traditional endocrine therapy and HER2-targeted therapy may not be effective for triple-negative breast cancer (TNBC). Therefore, chemotherapy has become one of the main treatment modalities. However, TNBC has a poor response to conventional chemotherapy and is prone to develop resistance. Immunotherapy including immune checkpoint inhibitors, has shown promise as an effective treatment modality for TNBC. Protein arginine methylation is prevalent among mammalian cells as a post-translational modification, governing numerous biological functions such as gene transcription, signal transduction, DNA damage repair, and RNA metabolism.5−7 It is catalyzed by the protein arginine methyltransferase (PRMT) family containing PRMT1 to PRMT9. PRMTs catalyze the transfer of a methyl group from S-adenosyl-L-methio

FAQs

What is iCARM1 and how does it relate to CARM1?

iCARM1 is a newly discovered CARM1 inhibitor designed to show better specificity and activity toward CARM1 than previously known inhibitors (EZM2302 and TP-064).

How does iCARM1 affect breast cancer cells at the molecular level?

iCARM1 suppresses expression of oncogenic estrogen/ERα-target genes, similar to CARM1 knockdown, while activating type I interferon signaling and interferon-induced genes (ISGs).

What therapeutic effects does iCARM1 show in vitro and in vivo?

iCARM1 potently suppresses breast cancer cell growth both in vitro and in vivo, and it demonstrates synergistic inhibition of breast tumor growth when combined with endocrine therapy drugs or etoposide.

Sep 21, 2026

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