Discovery of Diverse Small‐Molecule Inhibitors of Mammalian Sterile20‐like Kinase 3 (MST3)

Olesen, Sanne H.; Zhu, J.; Martin, Mathew P.; Schönbrunn, E.

doi:10.1002/cmdc.201600115

Cited by 23 publications

(43 citation statements)

References 46 publications

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“…43 The gene encoding human Myt1 kinase domain (Myt1-KD, residues 75–361) cloned in-frame with an N-terminal His 6 tag was received in a pNIC28-Bsa4 vector from Addgene (plasmid 39061). The gene encoding full-length Escherichia phage lambda serine/threonine-protein phosphatase (LAMBD, residues 1–221) was synthesized by GeneArt with optimized codon usage for E. coli protein expression and subcloned into pGEX-6p-2 vector with N-terminal GST tag.…”

Section: Methodsmentioning

confidence: 99%

Structural Basis of Wee Kinases Functionality and Inactivation by Diverse Small Molecule Inhibitors

et al. 2017

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Members of the Wee family of kinases negatively regulate the cell cycle via phosphorylation of CDK1 and are considered potential drug targets. Herein, we investigated the structure–function relationship of human Wee1, Wee2, and Myt1 (PKMYT1). Purified recombinant full-length proteins and kinase domain constructs differed substantially in phosphorylation states and catalytic competency, suggesting complex mechanisms of activation. A series of crystal structures reveal unique features that distinguish Wee1 and Wee2 from Myt1 and establish the structural basis of differential inhibition by the widely used Wee1 inhibitor MK-1775. Kinome profiling and cellular studies demonstrate that, in addition to Wee1 and Wee2, MK-1775 is an equally potent inhibitor of the polo-like kinase PLK1. Several previously unrecognized inhibitors of Wee kinases were discovered and characterized. Combined, the data provide a comprehensive view on the catalytic and structural properties of Wee kinases and a framework for the rational design of novel inhibitors thereof.

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Section: Methodsmentioning

confidence: 99%

Structural Basis of Wee Kinases Functionality and Inactivation by Diverse Small Molecule Inhibitors

et al. 2017

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“…For instance, it has been reported that indole-based compounds are inhibitors of serine/threonine-protein kinase B-raf (BRAF) 50 , 51 , B-cell lymphoma 6 (BCL-6) 52 , proto-oncogene tyrosine-protein kinase Src (c-Src) 53 , 54 and poly (ADP-ribose) polymerase (PARP) 55 , in clear agreement with our model. Similarly, indazole-based derivatives have been reported as inhibitors of BRAF 56 , phthalazinone core is present in inhibitors of PARP 57 , as well as quinoline scaffold is common in molecules acting as c-Src 58 and mammalian sterile20-like protein kinase 3 (MST3) inhibitors 59 . These evidences validate our iVS method in order to enable the identification of suitable targets for a particular molecular library, foreseeing successful biological investigation.…”

Section: Resultsmentioning

confidence: 99%

iVS analysis to evaluate the impact of scaffold diversity in the binding to cellular targets relevant in cancer

Cilibrizzi

Floresta

Abbate

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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This study reports the application of inverse virtual screening (iVS) methodologies to identify cellular proteins as suitable targets for a library of heterocyclic small-molecules, with potential pharmacological implications. Standard synthetic procedures allow facile generation of these ligands showing a high degree of core scaffold diversity. Specifically, we have computationally investigated the binding efficacy of the new series for target proteins which are involved in cancer pathogenesis. As a result, nine macromolecules demonstrated efficient binding interactions for the molecular dataset, in comparison to the co-crystallised ligand for each target. Moreover, the iVS analysis led us to confirm that 27 analogues have high affinity for one or more examined cellular proteins. The additional evaluation of ADME and drug score for selected hits also highlights their capability as drug candidates, demonstrating valuable leads for further structure optimisation and biological studies.

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“…For example, the efficacy of using ALK inhibitors in advanced nonsmall cell lung cancer with ALK rearrangement is evident in clinical trials . A study by Olesen et al identified 14 inhibitors, eight of which are in clinical trials or are Food and Drug Administration approved, that inhibited the enzymatic activity of STK24. Although further detailed investigations are required, STK24‐selective inhibitors are potential cancer therapeutics in tumours harbouring STK24 rearrangements.…”

Section: Discussionmentioning

confidence: 99%

Genomic and transcriptomic characterisation of undifferentiated pleomorphic sarcoma of bone

Ali

Niada

Brini

et al. 2018

The Journal of Pathology

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Undifferentiated pleomorphic sarcoma of bone (UPSb) is a rare primary bone sarcoma that lacks a specific line of differentiation. There is very little information about the genetic alterations leading to tumourigenesis or malignant transformation. Distinguishing between UPSb and other malignant bone sarcomas, including dedifferentiated chondrosarcoma and osteosarcoma, can be challenging due to overlapping features. To explore the genomic and transcriptomic landscape of UPSb tumours, whole‐exome sequencing (WES) and RNA sequencing (RNA‐Seq) were performed on UPSb tumours. All tumours lacked hotspot mutations in IDH1/2 132 or 172 codons, thereby excluding the diagnosis of dedifferentiated chondrosarcoma. Recurrent somatic mutations in TP53 were identified in four of 14 samples (29%). Moreover, recurrent mutations in histone chromatin remodelling genes, including H3F3A, ATRX and DOT1L, were identified in five of 14 samples (36%), highlighting the potential role of deregulated chromatin remodelling pathways in UPSb tumourigenesis. The majority of recurrent mutations in chromatin remodelling genes identified here are reported in COSMIC, including the H3F3A G34 and K36 hotspot residues. Copy number alteration analysis identified gains and losses in genes that have been previously altered in UPSb or UPS of soft tissue. Eight somatic gene fusions were identified by RNA‐Seq, two of which, CLTC‐VMP1 and FARP1‐STK24, were reported previously in multiple cancers. Five gene fusions were genomically characterised. Hierarchical clustering analysis, using RNA‐Seq data, distinctly clustered UPSb tumours from osteosarcoma and other sarcomas, thus molecularly distinguishing UPSb from other sarcomas. RNA‐Seq expression profiling analysis and quantitative reverse transcription‐polymerase chain reaction showed an elevated expression in FGF23, which can be a potential molecular biomarker for UPSb. To our knowledge, this study represents the first comprehensive WES and RNA‐Seq analysis of UPSb tumours revealing novel protein‐coding recurrent gene mutations, gene fusions and identifying a potential UPSb molecular biomarker, thereby broadening the understanding of the pathogenic mechanisms and highlighting the possibility of developing novel targeted therapeutics. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Discovery of Diverse Small‐Molecule Inhibitors of Mammalian Sterile20‐like Kinase 3 (MST3)

Cited by 23 publications

References 46 publications

Structural Basis of Wee Kinases Functionality and Inactivation by Diverse Small Molecule Inhibitors

Structural Basis of Wee Kinases Functionality and Inactivation by Diverse Small Molecule Inhibitors

iVS analysis to evaluate the impact of scaffold diversity in the binding to cellular targets relevant in cancer

Genomic and transcriptomic characterisation of undifferentiated pleomorphic sarcoma of bone

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