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.

eLifeQ1 · BIOLOGY

A chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion

Q1 · BIOLOGY

ArticleOA

Author: Zheng, Weihong ; Kim, Eui-jun ; Mazutis, Linas ; Ibáñez, Glorymar ; Lee, Jonghan P ; Wu, Hong ; Arrowsmith, Cheryl H ; Zeng, Hong ; Hajian, Taraneh ; Zhang, Tuo ; Li, Fengling ; Jiang, Ming ; Wang, Junyi ; Niu, Xiang ; Zhang, Zhenyu ; Dombrovski, Ludmila ; dela Seña, Carlo C ; Wang, Ke ; Vedadi, Masoud ; Cai, Xiao-Chuan ; Vivcharuk, Victor ; Brown, Peter J ; Qin, Li-Xuan ; Xu, Wei ; Dong, Aiping ; Min, Jinrong ; Chen, Shi ; Shi, Lei ; Deng, Haiteng ; Luo, Minkui ; Chen, Yuling ; Szewczyk, Magda ; Xiang, Jenny ; Barsyte, Dalia ; Zhang, Nawei

CARM1 is a cancer-relevant protein arginine methyltransferase that regulates many aspects of transcription. Its pharmacological inhibition is a promising anti-cancer strategy. Here SKI-73 (6a in this work) is presented as a CARM1 chemical probe with pro-drug properties. SKI-73 (6a) can rapidly penetrate cell membranes and then be processed into active inhibitors, which are retained intracellularly with 10-fold enrichment for several days. These compounds were characterized for their potency, selectivity, modes of action, and on-target engagement. SKI-73 (6a) recapitulates the effect of CARM1 knockout against breast cancer cell invasion. Single-cell RNA-seq analysis revealed that the SKI-73(6a)-associated reduction of invasiveness acts by altering epigenetic plasticity and suppressing the invasion-prone subpopulation. Interestingly, SKI-73 (6a) and CARM1 knockout alter the epigenetic plasticity with remarkable difference, suggesting distinct modes of action for small-molecule and genetic perturbations. We therefore discovered a CARM1-addiction mechanism of cancer metastasis and developed a chemical probe to target this process.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Preclinical	China	Xiamen University	07 May 2024

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