Xiao-Chuan Cai1, Tuo Zhang2, Eui-Jun Kim3, Ming Jiang1,4, Ke Wang1, Junyi Wang1, Shi Chen1,5, Nawei Zhang1,6, Hong Wu7, Fengling Li7, Carlo C Dela Seña7, Hong Zeng7, Victor Vivcharuk8, Xiang Niu9,10, Weihong Zheng1, Jonghan P Lee1,5, Yuling Chen11, Dalia Barsyte7, Magda Szewczyk7, Taraneh Hajian7, Glorymar Ibáñez1, Aiping Dong7, Ludmila Dombrovski7, Zhenyu Zhang6, Haiteng Deng7,11, Jinrong Min7,12, Cheryl H Arrowsmith7,13, Linas Mazutis9, Lei Shi8, Masoud Vedadi7,14, Peter J Brown7, Jenny Xiang2, Li-Xuan Qin15, Wei Xu3, Minkui Luo1,4. 1. Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States. 2. Genomics Resources Core Facility, Weill Cornell Medical College, Cornell University, New York, United States. 3. McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, United States. 4. Program of Pharmacology, Weill Cornell Medical College of Cornell University, New York, United States. 5. Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, United States. 6. Department of Obstetrics and Gynecology, Chaoyang Hospital, Affiliation Hospital of Capital Medical University, Beijing, China. 7. Structural Genomics Consortium, University of Toronto, Toronto, Canada. 8. Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States. 9. Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States. 10. Tri-Institutional PhD Program in Computational Biology and Medicine, Memorial Sloan Kettering Cancer Center, New York, United States. 11. Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing, China. 12. Department of Physiology, University of Toronto, Toronto, Canada. 13. Princess Margaret Cancer Centre, Department of Medical Biophysics, University of Toronto, Toronto, Canada. 14. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada. 15. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States.
Abstract
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.
class="Gene">CARM1 is a class="Chemical">pan class="Disease">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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