Kevin M. Cottrell, Douglas A. Whittington, Kimberly J. Briggs, Haris Jahic, Janid A. Ali, Alvaro J. Amor, Deepali Gotur, Matthew R. Tonini, Wenhai Zhang, Alan Huang, John P. Maxwell
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引用次数: 0
Abstract
Deletion of the MTAP gene leads to accumulation of the substrate of the MTAP protein, methylthioadenosine (MTA). MTA binds PRMT5 competitively with S-adenosyl-l-methionine (SAM), and selective inhibition of the PRMT5•MTA complex relative to the PRMT5•SAM complex can lead to selective killing of cancer cells with MTAP deletion. Herein, we describe the discovery of novel compounds using structure-based drug design to switch the mechanism of binding of known, SAM-cooperative PRMT5 inhibitors to an MTA-cooperative binding mechanism by occupying the portion of the SAM binding pocket in PRMT5 that is unoccupied when MTA is bound and hydrogen bonding to Arg368, thereby allowing them to selectively target MTAP-deleted cancer cells.
期刊介绍：
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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