558479-07-5Relevant academic research and scientific papers
Discovery of First-in-Class Protein Arginine Methyltransferase 5 (PRMT5) Degraders
Shen, Yudao,Gao, Guozhen,Yu, Xufen,Kim, Huensuk,Wang, Li,Xie, Ling,Schwarz, Megan,Chen, Xian,Guccione, Ernesto,Liu, Jing,Bedford, Mark T.,Jin, Jian
, p. 9977 - 9989 (2020/10/18)
The aberrant expression of protein arginine methyltransferase 5 (PRMT5) has been associated with multiple cancers. Using the proteolysis targeting chimera technology, we discovered a first-in-class PRMT5 degrader 15 (MS4322). Here, we report the design, synthesis, and characterization of compound 15 and two structurally similar controls 17 (MS4370) and 21 (MS4369), with impaired binding to the von Hippel-Lindau E3 ligase and PRMT5, respectively. Compound 15, but not 17 and 21, effectively reduced the PRMT5 protein level in MCF-7 cells. Our mechanism studies indicate that compound 15 degraded PRMT5 in an E3 ligase-and proteasome-dependent manner. Compound 15 also effectively reduced the PRMT5 protein level and inhibited growth in multiple cancer cell lines. Moreover, compound 15 was highly selective for PRMT5 in a global proteomic study and exhibited good plasma exposure in mice. Collectively, compound 15 and its two controls 17 and 21 are valuable chemical tools for exploring the PRMT5 functions in health and disease.
BH4 ANTAGONISTS AND METHODS RELATED THERETO
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Page/Page column 47-48, (2015/11/27)
The disclosure relates to BH4 inhibitors and therapeutic uses relates thereto. In certain embodiments, the disclosure relates to methods of treating or preventing cancer, such as lung cancer, comprising administering therapeutically effective amount of a pharmaceutical composition comprising a compound disclosed herein or pharmaceutically acceptable salt to a subject in need thereof.
1,3-Diaminopropan-2-ol Sulfonamides as potent and selective inhibitors of the glycine transporter type 1
Rahman, Shahzad S.,Coulton, Steven,Herdon, Hugh J.,Joiner, Graham F.,Jin, Jian,Porter, Roderick A.
, p. 1741 - 1745 (2008/02/11)
High throughput screening led to the discovery of a novel series of 1,3-diaminopropan-2-ol sulfonamides as selective GlyT-1 inhibitors. Structure-activity relationships of this novel series and optimisation of the initial hit that led to the identificatio
GLYT1 TRANSPORTER INHIBITORS
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Page/Page column 52-53, (2010/02/12)
The invention provides a compound of formula (I): or a salt, solvate or a physiologically functional derivative thereof, wherein R1 to R10 are as defined in the specification and uses of such compounds. The compounds inhibit GlyT1 transporters and are useful in the treatment of certain neurological and neuropsychiatric disorders, including schizophrenia.
