Structure-Based Design of a Novel SMYD3 Inhibitor that Bridges the SAM-and MEKK2-Binding Pockets

Aller, Glenn S. Van; Graves, Alan P.; Elkins, P.A.; Bonnette, William G.; McDevitt, Patrick; Zappacosta, Francesca; Annan, Roland S.; Dean, Tony W.; Su, Dai‐Shi; Carpenter, Christopher L.; Mohammad, Helai P.; Kruger, Ryan G.

doi:10.1016/j.str.2016.03.010

Cited by 53 publications

(47 citation statements)

References 23 publications

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“…In 2016, Van Aller and co-workers reported the structure-based design of a novel SMYD3 inhibitor. 184 A cocrystal structure of SMYD3 and a MAP3K2 peptide (residues YDNPIFEKFGKGGTY) was solved (PDB ID: 5HQ8), and a previously unidentified ternary complex composed of SMYD3, substrate, and SAH was observed. It was postulated that the methyl transfer reaction catalyzed by SMYD3 proceeds through a ternary complex mechanism and a compound that contains portions of both SAH and MAP3K2 K260 could provide a useful bisubstrate inhibitor.…”

Section: Protein Methyltransferasesmentioning

confidence: 99%

Inhibitors of Protein Methyltransferases and Demethylases

2017

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Post-translational modifications of histones by protein methyltransferases (PMTs) and histone demethylases (KDMs) play an important role in the regulation of gene expression and transcription and are implicated in cancer and many other diseases. Many of these enzymes also target various nonhistone proteins impacting numerous crucial biological pathways. Given their key biological functions and implications in human diseases, there has been a growing interest in assessing these enzymes as potential therapeutic targets. Consequently, discovering and developing inhibitors of these enzymes has become a very active and fast-growing research area over the past decade. In this review, we cover the discovery, characterization, and biological application of inhibitors of PMTs and KDMs with emphasis on key advancements in the field. We also discuss challenges, opportunities, and future directions in this emerging, exciting research field.

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Section: Protein Methyltransferasesmentioning

confidence: 99%

Inhibitors of Protein Methyltransferases and Demethylases

2017

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“…Owing to the poor membrane permeability, GSK2807 cannot be used in in vivo studies. Nevertheless, it represents a powerful tool to gain insight into SMYD3 catalytic and kinetic mechanisms [96].…”

Section: Design and Testing Of Smyd3 Inhibitorsmentioning

confidence: 99%

SMYD3: An Oncogenic Driver Targeting Epigenetic Regulation and Signaling Pathways

Bottino

Peserico

Simone

et al. 2020

Cancers

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SMYD3 is a member of the SMYD lysine methylase family and plays an important role in the methylation of various histone and non-histone targets. Aberrant SMYD3 expression contributes to carcinogenesis and SMYD3 upregulation was proposed as a prognostic marker in various solid cancers. Here we summarize SMYD3-mediated regulatory mechanisms, which are implicated in the pathophysiology of cancer, as drivers of distinct oncogenic pathways. We describe SMYD3-dependent mechanisms affecting cancer progression, highlighting SMYD3 interplay with proteins and RNAs involved in the regulation of cancer cell proliferation, migration and invasion. We also address the effectiveness and mechanisms of action for the currently available SMYD3 inhibitors. The findings analyzed herein demonstrate that a complex network of SMYD3-mediated cytoplasmic and nuclear interactions promote oncogenesis across different cancer types. These evidences depict SMYD3 as a modulator of the transcriptional response and of key signaling pathways, orchestrating multiple oncogenic inputs and ultimately, promoting transcriptional reprogramming and tumor transformation. Further insights into the oncogenic role of SMYD3 and its targeting of different synergistic oncogenic signals may be beneficial for effective cancer treatment.

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“…Although the quest to develop epigenetic drugs poses certain challenges (Audia and Campbell, 2016), this is an area of intense interest and several HMTs including EZH2, MLL3 and NSDs have been put forward as rational drug targets (Chen et al., 2014; Katoh, 2016). Several potent and selective SAM‐competitive inhibitors of SMYD3 have been described (Van Aller et al., 2016), and their clinical utility certainly warrants more investigation. Small molecule inhibitors for several PRMTs have been reviewed elsewhere (Song et al., 2016), and they represent an exciting class of potential anti‐cancer drugs.…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of histone methyltransferases in breast cancer – Opportunities for new targeted therapies?

Michalak

Visvader

2016

Molecular Oncology

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Histone methyltransferases (HMTs) catalyze the methylation of lysine and arginine residues on histone tails and non-histone targets. These important post-translational modifications are exquisitely regulated and affect chromatin compaction and transcriptional programs leading to diverse biological outcomes. There is accumulating evidence that genetic alterations of several HMTs impinge on oncogenic or tumor-suppressor functions and influence both cancer initiation and progression. HMTs therefore represent an opportunity for therapeutic targeting in those patients with tumors in which HMTs are dysregulated, to reverse the histone marks and transcriptional programs associated with aggressive tumor behavior. In this review, we describe the known histone methyltransferases and their emerging roles in breast cancer tumorigenesis.

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Structure-Based Design of a Novel SMYD3 Inhibitor that Bridges the SAM-and MEKK2-Binding Pockets

Cited by 53 publications

References 23 publications

Inhibitors of Protein Methyltransferases and Demethylases

Inhibitors of Protein Methyltransferases and Demethylases

SMYD3: An Oncogenic Driver Targeting Epigenetic Regulation and Signaling Pathways

Dysregulation of histone methyltransferases in breast cancer – Opportunities for new targeted therapies?

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