BIX-01294 inhibits oncoproteins NSD1, NSD2 and NSD3

Morishita, Masaki; Mevius, Damiaan E. H. F.; Shen, Yunpeng; Zhao, Shuyu; Luccio, Eric di

doi:10.1007/s00044-017-1909-7

Cited by 29 publications

(36 citation statements)

References 27 publications

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“…This is in contrast to other members in the protein methyltransferase superfamily, many of which have in vitro and/or in vivo tool compounds available [ 52 ] and three protein methyltransferases have compounds that have reached the clinic (EZH2, DOT1L, PRMT5; www.clinicaltrials.gov ). Recently, two structurally related G9a inhibitors, UNC0638 [ 39 ] and BIX-01294 [ 40 ], have been reported to bind or inhibit one or more NSD family proteins. However, computational models of binding of BIX-01294 to the NSD co-enzyme site [ 40 ] are in direct contrast to the NMR data with UNC0638 indicating the compound interacted with the N-terminus of the SET domain construct [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, two structurally related G9a inhibitors, UNC0638 [ 39 ] and BIX-01294 [ 40 ], have been reported to bind or inhibit one or more NSD family proteins. However, computational models of binding of BIX-01294 to the NSD co-enzyme site [ 40 ] are in direct contrast to the NMR data with UNC0638 indicating the compound interacted with the N-terminus of the SET domain construct [ 39 ]. It is possible that these two compounds differ in their interactions with WHSC1 and other NSD family members.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibitors based on sinefungin, a substrate analog of the cofactor SAM, have been reported for WHSC1 but structures of these compounds were reported in a closely related enzyme, SETD2, rather than in an NSD family protein [ 39 ]. Additional studies with two known inhibitors of G9a, UNC0638 [ 39 ] and BIX-01294 [ 40 ], have not shown experimental evidence of specific binding of these compounds to the active site of the NSD family members. A specific inhibitor for any member of the NSD family would be a valuable addition to the chemical library for protein methyltransferases.…”

Section: Introductionmentioning

confidence: 99%

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Identification of a peptide inhibitor for the histone methyltransferase WHSC1

et al. 2018

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WHSC1 is a histone methyltransferase that is responsible for mono- and dimethylation of lysine 36 on histone H3 and has been implicated as a driver in a variety of hematological and solid tumors. Currently, there is a complete lack of validated chemical matter for this important drug discovery target. Herein we report on the first fully validated WHSC1 inhibitor, PTD2, a norleucine-containing peptide derived from the histone H4 sequence. This peptide exhibits micromolar affinity towards WHSC1 in biochemical and biophysical assays. Furthermore, a crystal structure was solved with the peptide in complex with SAM and the SET domain of WHSC1L1. This inhibitor is an important first step in creating potent, selective WHSC1 tool compounds for the purposes of understanding the complex biology in relation to human disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of a peptide inhibitor for the histone methyltransferase WHSC1

et al. 2018

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“…BIX-01294, a selective and specific inhibitor of MMSET [ 13 ], has been shown to impair cell growth and sphere formation of hepatocellular carcinoma cells [ 14 ]. To study whether pharmacological inhibition of MMSET activity can inhibit EC cell invasion and sphere formation, we treated HEC-1 cells with various concentrations (0, 1, 5 μM) of BIX-01294.…”

Section: Resultsmentioning

confidence: 99%

miR-34a, miR-424 and miR-513 inhibit MMSET expression to repress endometrial cancer cell invasion and sphere formation

et al. 2018

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Although the oncogene MMSET (also known as NSD2 or WHSC1) has an essential role in malignancies, its impact on human endometrial cancer (EC) metastasis and the molecular mechanism of MMSET regulation are largely unknown. We report that MMSET was markedly upregulated in EC cell lines and EC tissues, and was significantly associated with poor survival in EC. MMSET overexpression greatly promoted EC cell invasion and sphere formation, whereas inhibition of MMSET reduced EC cell invasion and sphere formation. Importantly, Twist1 was required for MMSET-induced EC cell invasion and sphere formation. Moreover, we demonstrate that miR-34a, miR-424 and miR-513 directly modulate MMSET expression to attenuate the invasion and sphere formation capacity of EC cells. miR-34a, miR-424 and miR-513 were down-regulated in EC compared with normal tissue, and reduced expression of miR-34a, miR-424 and miR-513 was clinically associated with a poorer prognosis in EC patients. Furthermore, specific inhibition of MMET with BIX-01294 led to decreased EC cell invasion and impaired sphere formation. These findings suggest a pro-metastatic role for MMSET in EC and reveal that the repression of miR-34a, miR-424 and miR-513 contributes to the overexpression of MMSET during EC metastasis.

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“…All three compounds inhibit NSD1 higher than 50% at 10 µM and in a dose-response manner, especially CM-679. Interestingly, very recently it was shown that the EHMT2 inhibitor BIX-01294 does also inhibit NSD1 (IC 50 = 112 µM) [ 44 ]. Taken altogether, apart from the validation of the PKMT-CoINPocket approach, these results open the door to the repurposing of EHMT2 inhibitors towards NSD1, at least to serve as starting points for potency optimization.…”

Section: Resultsmentioning

confidence: 99%

Novel pharmacological maps of protein lysine methyltransferases: key for target deorphanization

2018

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Epigenetic therapies are being investigated for the treatment of cancer, cognitive disorders, metabolic alterations and autoinmune diseases. Among the different epigenetic target families, protein lysine methyltransferases (PKMTs), are especially interesting because it is believed that their inhibition may be highly specific at the functional level. Despite its relevance, there are currently known inhibitors against only 10 out of the 50 SET-domain containing members of the PKMT family. Accordingly, the identification of chemical probes for the validation of the therapeutic impact of epigenetic modulation is key. Moreover, little is known about the mechanisms that dictate their substrate specificity and ligand selectivity. Consequently, it is desirable to explore novel methods to characterize the pharmacological similarity of PKMTs, going beyond classical phylogenetic relationships. Such characterization would enable the prediction of ligand off-target effects caused by lack of ligand selectivity and the repurposing of known compounds against alternative targets. This is particularly relevant in the case of orphan targets with unreported inhibitors. Here, we first perform a systematic study of binding modes of cofactor and substrate bound ligands with all available SET domain-containing PKMTs. Protein ligand interaction fingerprints were applied to identify conserved hot spots and contact-specific residues across subfamilies at each binding site; a relevant analysis for guiding the design of novel, selective compounds. Then, a recently described methodology (GPCR-CoINPocket) that incorporates ligand contact information into classical alignment-based comparisons was applied to the entire family of 50 SET-containing proteins to devise pharmacological similarities between them. The main advantage of this approach is that it is not restricted to proteins for which crystallographic data with bound ligands is available. The resulting family organization from the separate analysis of both sites (cofactor and substrate) was retrospectively and prospectively validated. Of note, three hits (inhibition > 50% at 10 µM) were identified for the orphan NSD1.Electronic supplementary materialThe online version of this article (10.1186/s13321-018-0288-5) contains supplementary material, which is available to authorized users.

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BIX-01294 inhibits oncoproteins NSD1, NSD2 and NSD3

Cited by 29 publications

References 27 publications

Identification of a peptide inhibitor for the histone methyltransferase WHSC1

Identification of a peptide inhibitor for the histone methyltransferase WHSC1

miR-34a, miR-424 and miR-513 inhibit MMSET expression to repress endometrial cancer cell invasion and sphere formation

Novel pharmacological maps of protein lysine methyltransferases: key for target deorphanization

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