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Discovery of a Potent and Dual-Selective Bisubstrate Inhibitor for Protein Arginine Methyltransferase 4/5

Ayad A. Al-Hamashi, Dongxing Chen, Youchao Deng, Guangping Dong, View ORCID ProfileRong Huang
doi: https://doi.org/10.1101/2020.09.05.283978
Ayad A. Al-Hamashi
aDepartment of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, United States
bDepartment of Pharmaceutical Chemistry, College of Pharmacy, Bab-almoadham, Baghdad, Iraq
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Dongxing Chen
aDepartment of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, United States
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Youchao Deng
aDepartment of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, United States
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Guangping Dong
aDepartment of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, United States
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Rong Huang
aDepartment of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, United States
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  • ORCID record for Rong Huang
  • For correspondence: huang-r@purdue.edu
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Abstract

Protein arginine methyltransferases (PRMTs) have been implicated in the progression of many diseases. Understanding substrate recognition and specificity of individual PRMT would facilitate the discovery of selective inhibitors towards future drug discovery. Herein, we reported the design and synthesis of bisubstrate analogues for PRMTs that incorporate a S-adenosylmethionine (SAM) analogue moiety and a tripeptide through an alkyl substituted guanidino group. Compound AH237 is a potent and selective inhibitor for PRMT4 and PRMT5 with a half-maximal inhibition concentration (IC50) of 2.8 nM and <1.5 nM, respectively. Computational studies provided a plausible explanation for the high potency and selectivity of AH237 for PRMT4/5 over other 40 methyltransferases. This proof-of-principle study outlines an applicable strategy to develop potent and selective bisubstrate inhibitors for PRMTs, providing valuable probes for future structural studies.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 06, 2020.
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Discovery of a Potent and Dual-Selective Bisubstrate Inhibitor for Protein Arginine Methyltransferase 4/5
Ayad A. Al-Hamashi, Dongxing Chen, Youchao Deng, Guangping Dong, Rong Huang
bioRxiv 2020.09.05.283978; doi: https://doi.org/10.1101/2020.09.05.283978
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Discovery of a Potent and Dual-Selective Bisubstrate Inhibitor for Protein Arginine Methyltransferase 4/5
Ayad A. Al-Hamashi, Dongxing Chen, Youchao Deng, Guangping Dong, Rong Huang
bioRxiv 2020.09.05.283978; doi: https://doi.org/10.1101/2020.09.05.283978

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