Rational Design and Synthesis of Selective PRMT4 Inhibitors: A New Chemotype for Development of Cancer Therapeutics**

Abstract

Protein arginine N‐methyl transferase 4 (PRMT4) asymmetrically dimethylates the arginine residues of histone H3 and nonhistone proteins. The overexpression of PRMT4 in several cancers has stimulated interest in the discovery of inhibitors as biological tools and, potentially, therapeutics. Although several PRMT4 inhibitors have been reported, most display poor selectivity against other members of the PRMT family of methyl transferases. Herein, we report the structure‐based design of a new class of alanine‐containing 3‐arylindoles as potent and selective PRMT4 inhibitors, and describe key structure–activity relationships for this class of compounds.

Structure-Based Discovery of Potent CARM1 Inhibitors for Solid Tumor and Cancer Immunology Therapy

“…The title compound was obtained as a colorless oil in 17% yield from 57e using a method similar to that described for compound 9. (38). The title compound was obtained as a colorless oil in 38% yield from 57f using a method similar to that described for compound 9.…”

“…Encouraged by the tempting potential, the search for potent and selective CARM1 inhibitors has attracted considerable attention in the pharmaceutical industry and academic institutions. Although the exact mechanism underlying the oncogenicity of CARM1 is not well understood, several selective CARM1 inhibitors have been identified. , These small-molecule inhibitors can be grouped into three categories based on the different arginine mimics, including alanine amide, − ethylenediamino, − and 1-amino-3-phenoxy-propan-2-ol , (Figure ). Inhibitors with alanine amide moiety such as compound 1 possess excellent potency and selectivity, while the poor permeability and metabolic stability limit its further exploitation.…”

Turning Nonselective Inhibitors of Type I Protein Arginine Methyltransferases into Potent and Selective Inhibitors of Protein Arginine Methyltransferase 4 through a Deconstruction–Reconstruction and Fragment-Growing Approach

“…Also, viral proteins from several viruses are methylated by PRMTs, − including SARS-CoV-2 nucleocapsid (N) protein, the methylation of which at residues R95 and R177 is crucial for viral replication . Indeed, over the past 15 years the medicinal chemistry community has paid a growing attention to PRMTs, ,,− in particular to PRMT5 (with a few inhibitors in clinical trials) ,− and to type I enzymes (both pan-type I ,− and selective ,− ).…”

Connecting GSK-3β Inhibitory Activity with IKK-β or ROCK-1 Inhibition to Target Tau Aggregation and Neuroinflammation in Alzheimer’s Disease—Discovery, In Vitro and In Cellulo Activity of Thiazole-Based Inhibitors

“…In further studies, we chose the most potent inhibitors selectively targeting GSK-3β (39, 41, 48-50) and IKK-β (58), as well as GSK-3β inhibitors with additional ROCK-1 (62) and IKK-β/ROCK-1 (40, 60) inhibitory potencies. We assessed their cytotoxic effects at five concentrations (0.1, 1, 10, 50, and 100 µM) in HT-22 (mouse hippocampal neuronal cells) and BV-2 (mouse microglial cells) cell lines using a fluorometric assay with PrestoBlue™ cell viability reagent (Table 4, Table S2 in the SI).…”