- Discovery of First-in-Class Protein Arginine Methyltransferase 5 (PRMT5) Degraders
-
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.
- 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
-
-
Read Online
- A Flow Process Built upon a Batch Foundation - Preparation of a Key Amino Alcohol Intermediate via Multistage Continuous Synthesis
-
This paper describes recent efforts to apply flow technology in the preparation of the key amino alcohol intermediate 3b so as to address manufacturability issues present in the batch process of a PRMT5 inhibitor. The continuous process, one of the first reported pharmaceutical processes to use aqueous NH4OH in flow, eliminates an isolation and the use of dichloromethane in the workup and improves reaction time >140-fold compared with the batch process to deliver multigram quantities of 3b in 60-65% isolated yield with >99 HPLC area % and >99% ee. While the flow process greatly increases the efficiency compared with the batch process, small-scale batch experiments were crucial in gaining reaction understanding to increase the kinetics and minimize impurity formation. The holistic process design underscores our belief that large-scale flow processes are built upon the knowledge gained through well-chosen small-scale batch experiments.
- Lim, John Jin,Arrington, Kenneth,Dunn, Anna L.,Leitch, David C.,Andrews, Ian,Curtis, Neil R.,Hughes, Mark J.,Tray, Daniel R.,Wade, Charles E.,Whiting, Matthew P.,Goss, Charles,Liu, Yangmu Chloe,Roesch, Brian M.
-
p. 1927 - 1937
(2020/01/31)
-
- PRMT5 INHIBITORS AND USES THEREOF
-
Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting PRMT5 activity. Methods of using the compounds for treating PRMT5-mediated disorders are also described.
- -
-
Paragraph 0218-0219
(2019/04/05)
-
- HETEROCYCLIC COMPOUNDS AS PRMT5 INHIBITORS
-
The compounds of Formula I, Formula Ia, and Formula Ib are described herein along with their analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites, and prodrugs thereof. These compounds inhibit PRMT5 and are useful as therpeautic or ameliorating agent for diseases that are involved in cellular growth such as malignant tumors, schizophrenia, Alzheimer's disease, Parkinson's disease and the like.
- -
-
Paragraph 000145
(2019/06/11)
-
- Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666
-
The recent publication of a potent and selective inhibitor of protein methyltransferase 5 (PRMT5) provides the scientific community with in vivo-active tool compound EPZ015666 (GSK3235025) to probe the underlying pharmacology of this key enzyme. Herein, we report the design and optimization strategies employed on an initial hit compound with poor in vitro clearance to yield in vivo tool compound EPZ015666 and an additional potent in vitro tool molecule EPZ015866 (GSK3203591).
- Duncan, Kenneth W.,Rioux, Nathalie,Boriack-Sjodin, P. Ann,Munchhof, Michael J.,Reiter, Lawrence A.,Majer, Christina R.,Jin, Lei,Johnston, L. Danielle,Chan-Penebre, Elayne,Kuplast, Kristy G.,Porter Scott, Margaret,Pollock, Roy M.,Waters, Nigel J.,Smith, Jesse J.,Moyer, Mikel P.,Copeland, Robert A.,Chesworth, Richard
-
supporting information
p. 162 - 166
(2016/03/01)
-
- CRYSTALLINE SALTS OF (S)-6-((1-ACETYLPIPERIDIN-4-YL)AMINO)-N-(3-(3,4-DIHYDROISOQUINOLIN-2(1H)-YL)-2-HYDROXYPROPYL)PYRIMIDINE-4-CARBOXAMIDE
-
Disclosed are novel crystalline salts of (S)-6-((1-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide and pharmaceutical compositions containing the same. Also disclosed are processes for the prepar
- -
-
Page/Page column 22; 23
(2016/01/25)
-
- PRMT5 INHIBITORS CONTAINING A DIHYDRO- OR TETRAHYDROISOQUINOLINE AND USES THEREOF
-
Described herein are compounds of Formula (A), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting PRMT5 activity. Methods of using the compounds for treating PRMT5- mediated disorders are also described.
- -
-
Paragraph 00254
(2014/07/08)
-