Tag: M.W=500-550

Tang, Bowen published the artcileInsights into the stereoselectivity of human SETD7 methyltransferase, Recommanded Product: (R)-8-Fluoro-N-(1-oxo-1-(pyrrolidin-1-yl)-3-(3-(trifluoromethyl)phenyl)propan-2-yl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide hydrochloride, the publication is RSC Advances (2019), 9(16), 9218-9227, database is CAplus and MEDLINE.

Human SETD7 methyltransferase (hSETD7) is involved in a wide range of physiol. processes, and has been considered as a significant target to develop new drugs. (R)-PFI-2, one hSETD7 inhibitor, could bind to the pocket of substrates with potent (low nanomolar) activity and high selectivity, while its enantiomer (S)-PFI-2 showed 500-fold less activity in IC₅₀ determination Why do this pair of enantiomers, with nearly identical structures, exert tremendously different inhibitory activity. We performed a total of 900 ns long-timescale mol. dynamics (MD) simulations and 80 ps hybrid quantum mechanics/mol. mechanics (QM/MM) MD simulations to understand the mol. mechanism of the stereoselectivity of hSETD7. For each SAM/hSETD7/PFI-2 system, we characterized and compared the residual fluctuation of hSETD7, and generated mol. interaction fingerprints (IFP) to exemplify the propensities of SAM/hSETD7-inhibitor interactions. Based on the QM/MM MD, we accurately captured the difference of hydrogen bonds between the SAM/hSETD7/(R)-PFI-2 and SAM/hSETD7/(S)-PFI-2 systems. Especially the strength of the hydrogen bond between G336 and two inhibitors, which determines the stability of the post-SET loop. The energy barrier for (S)-PFI-2 was much bigger than (R)-PFI-2 from global min. to bioactive conformation as the potential energy surface scanning (PES) showed. Moreover, by estimating the binding affinity and phylogenetic tree anal., we discovered 16 hotspots were essential for binding both enantiomers but the specific mode of interaction between these hotspots and enantiomorphs is different. Our findings reveal the effect of chirality on the inhibition activity of hSETD7 in detail, and provide valuable information for hSETD7 structure-based drug development.

RSC Advances published new progress about 1627607-87-7. 1627607-87-7 belongs to tetrahydroisoquinoline, auxiliary class Epigenetics,Histone Methyltransferase, name is (R)-8-Fluoro-N-(1-oxo-1-(pyrrolidin-1-yl)-3-(3-(trifluoromethyl)phenyl)propan-2-yl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide hydrochloride, and the molecular formula is C13H16O2, Recommanded Product: (R)-8-Fluoro-N-(1-oxo-1-(pyrrolidin-1-yl)-3-(3-(trifluoromethyl)phenyl)propan-2-yl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide hydrochloride.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydroisoquinoline,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

Barsyte-Lovejoy, Dalia published the artcile(R)-PFI-2 is a potent and selective inhibitor of SETD7 methyltransferase activity in cells, Recommanded Product: (R)-8-Fluoro-N-(1-oxo-1-(pyrrolidin-1-yl)-3-(3-(trifluoromethyl)phenyl)propan-2-yl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide hydrochloride, the publication is Proceedings of the National Academy of Sciences of the United States of America (2014), 111(35), 12853-12858, database is CAplus and MEDLINE.

SET domain containing (lysine methyltransferase) 7 (SETD7) is implicated in multiple signaling and disease related pathways with a broad diversity of reported substrates. Here, we report the discovery of (R)-PFI-2-a first-in-class, potent (Kiapp = 0.33 nM), selective, and cell-active inhibitor of the methyltransferase activity of human SETD7-and its 500-fold less active enantiomer, (S)-PFI-2. (R)-PFI-2 exhibits an unusual cofactor-dependent and substrate-competitive inhibitory mechanism by occupying the substrate peptide binding groove of SETD7, including the catalytic lysine-binding channel, and by making direct contact with the donor Me group of the cofactor, S-adenosylmethionine. Chemoproteomics experiments using a biotinylated derivative of (R)-PFI-2 demonstrated dose-dependent competition for binding to endogenous SETD7 in MCF7 cells pretreated with (R)-PFI-2. In murine embryonic fibroblasts, (R)-PFI-2 treatment phenocopied the effects of Setd7 deficiency on Hippo pathway signaling, via modulation of the transcriptional coactivator Yes-associated protein (YAP) and regulation of YAP target genes. In confluent MCF7 cells, (R)-PFI-2 rapidly altered YAP localization, suggesting continuous and dynamic regulation of YAP by the methyltransferase activity of SETD7. These data establish (R)-PFI-2 and related compounds as a valuable tool-kit for the study of the diverse roles of SETD7 in cells and further validate protein methyltransferases as a druggable target class.

Proceedings of the National Academy of Sciences of the United States of America published new progress about 1627607-87-7. 1627607-87-7 belongs to tetrahydroisoquinoline, auxiliary class Epigenetics,Histone Methyltransferase, name is (R)-8-Fluoro-N-(1-oxo-1-(pyrrolidin-1-yl)-3-(3-(trifluoromethyl)phenyl)propan-2-yl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide hydrochloride, and the molecular formula is C23H26ClF4N3O3S, Recommanded Product: (R)-8-Fluoro-N-(1-oxo-1-(pyrrolidin-1-yl)-3-(3-(trifluoromethyl)phenyl)propan-2-yl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide hydrochloride.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydroisoquinoline,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

Hamidi, Tewfik published the artcileIdentification of Rpl29 as a major substrate of the lysine methyltransferase Set7/9, Application In Synthesis of 1627607-87-7, the publication is Journal of Biological Chemistry (2018), 293(33), 12770-12780, database is CAplus and MEDLINE.

Set7/9 (also known as Set7, Set9, Setd7, and Kmt7) is a lysine methyltransferase that catalyzes the methylation of multiple substrates, including histone H3 and non-histone proteins. Although not essential for normal development and physiol., Set7/9-mediated methylation events play important roles in regulating cellular pathways involved in various human diseases, making Set7/9 a promising therapeutic target. Multiple Set7/9 inhibitors have been developed, which exhibit varying degrees of potency and selectivity in vitro. However, validation of these compounds in vivo has been hampered by the lack of a reliable cellular biomarker for Set7/9 activity. Here, we report the identification of Rpl29, a ribosomal protein abundantly expressed in all cell types, as a major substrate of Set7/9. We show that Rpl29 lysine 5 (Rpl29K5) is methylated exclusively by Set7/9 and can be demethylated by Lsd1 (also known as Kdm1a). Rpl29 is not a core component of the ribosome translational machinery and plays a regulatory role in translation efficiency. Our results indicate that Rpl29 methylation has no effect on global protein synthesis but affects Rpl29 subcellular localization. Using an Rpl29 methylation-specific antibody, we demonstrate that Rpl29K5 methylation is present ubiquitously and validate that (R)-PFI-2, a Set7/9 inhibitor, efficiently reduces Rpl29K5 methylation in cell lines. Thus, Rpl29 methylation can serve as a specific cellular biomarker for measuring Set7/9 activity.

Journal of Biological Chemistry published new progress about 1627607-87-7. 1627607-87-7 belongs to tetrahydroisoquinoline, auxiliary class Epigenetics,Histone Methyltransferase, name is (R)-8-Fluoro-N-(1-oxo-1-(pyrrolidin-1-yl)-3-(3-(trifluoromethyl)phenyl)propan-2-yl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide hydrochloride, and the molecular formula is C23H26ClF4N3O3S, Application In Synthesis of 1627607-87-7.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydroisoquinoline,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem