Cytotoxic activity of Shp2 inhibitor fumosorinone in human cancer cells

Chen, Chuan; Xue, Tongdan; Fan, Peng; Meng, Linlin; Wei, Jingjing; Luo, Du‐Qiang

doi:10.3892/ol.2018.8593

Cited by 6 publications

(5 citation statements)

References 38 publications

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“…To determine whether hit compounds have effects on cell growth, SHP2-dependent MDA-MB-231 and HeLa cells were treated with gradient concentrations of test compounds 38 , 39 . Results shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

A multifunctional cross-validation high-throughput screening protocol enabling the discovery of new SHP2 inhibitors

Song

Zhao

et al. 2021

Acta Pharmaceutica Sinica B

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The protein tyrosine phosphatase Src homology phosphotyrosyl phosphatase 2 (SHP2) is implicated in various cancers, and targeting SHP2 has become a promising therapeutic approach. We herein described a robust cross-validation high-throughput screening protocol that combined the fluorescence-based enzyme assay and the conformation-dependent thermal shift assay for the discovery of SHP2 inhibitors. The established method can effectively exclude the false positive SHP2 inhibitors with fluorescence interference and was also successfully employed to identify new protein tyrosine phosphatase domain of SHP2 (SHP2-PTP) and allosteric inhibitors. Of note, this protocol showed potential for identifying SHP2 inhibitors against cancer-associated SHP2 mutation SHP2-E76A. After initial screening of our in-house compound library (∼2300 compounds), we identified 4 new SHP2-PTP inhibitors (0.17% hit rate) and 28 novel allosteric SHP2 inhibitors (1.22% hit rate), of which SYK-85 and WS-635 effectively inhibited SHP2-PTP (SYK-85: IC 50 = 0.32 μmol/L; WS-635: IC 50 = 4.13 μmol/L) and thus represent novel scaffolds for designing new SHP2-PTP inhibitors. TK-147, an allosteric inhibitor, inhibited SHP2 potently (IC 50 = 0.25 μmol/L). In structure, TK-147 could be regarded as a bioisostere of the well characterized SHP2 inhibitor SHP-099, highlighting the essential structural elements for allosteric inhibition of SHP2. The principle underlying the cross-validation protocol is potentially feasible to identify allosteric inhibitors or those inactivating mutants of other proteins.

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Section: Resultsmentioning

confidence: 99%

A multifunctional cross-validation high-throughput screening protocol enabling the discovery of new SHP2 inhibitors

Song

Zhao

et al. 2021

Acta Pharmaceutica Sinica B

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“…Additionally, fumosorinone, a terpene compound isolated from the same fungal species, could act as a classic non-competitive inhibitor of protein tyrosine phosphatase 1B (PTP1B), indicating that the compound could function in medicine for the clinical treatment of diabetes (type II) and other related metabolic disorders (Liu et al, 2015). This same compound has also been related to cytotoxicity against human cancer lines (Chen et al, 2018). Peroxyergosterol is a biocompound isolated from another strain of I. fumosorosea and has been tested for various bioactivities, including its cytotoxicity against cancer cells (Sheu et al, 2000), apoptosis of human leukemia cells (Takei et al, 2005), and potential production of vitamin A (Zhang et al, 2013).…”

Section: Endophytic Fungi As Good Sources Of Pharmaceutical Productsmentioning

confidence: 99%

Model Application of Entomopathogenic Fungi as Alternatives to Chemical Pesticides: Prospects, Challenges, and Insights for Next-Generation Sustainable Agriculture

et al. 2021

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In the past few decades, the control of pests and diseases of cultivated plants using natural and biological measures has drawn increasing attention in the quest to reduce the level of dependence on chemical products for agricultural production. The use of living organisms, predators, parasitoids, and microorganisms, such as viruses, bacteria, and fungi, has proven to be a viable and sustainable pest management technique. Among the aforementioned, fungi, most importantly the insect-pathogenic species, have been in use for more than 150years. These include the most popular strains belonging to the genera Beauveria, Metarhizium, Isaria, Hirsutella, and Lecanicillium. Their application is usually through an inundative approach, which inherently involves exposure of the fungal spores to unfavorable humidity, temperature, and solar radiation conditions. These abiotic factors reduce the persistence and efficacy of these insect-pathogenic fungi. Despite these limitations, over 170 strains have been formulated as mycopesticides and are available for commercial use. In the last few decades, numerous studies have suggested that these species of entomopathogenic fungi (EPF) offer far more benefits and have broader ecological functions than hitherto presumed. For instance, aside from their roles as insect killers, it has been well established that they also colonize various host plants and, hence, provide other benefits including plant pathogen antagonism and plant growth promotion and serve as sources of novel bioactive compounds and secondary metabolites, etc. In this light, the potential of EPF as alternatives or perhaps as supplements to chemical pesticides in plant protection is discussed in this review. The paper highlights the numerous benefits associated with endophytic fungal entomopathogen and host plant associations, the mechanisms involved in mediating plant defense against pests and pathogens, and the general limitations to the use of EPF in plant protection. A deeper understanding of these plant host-fungus-insect relationships could help unveil the hidden potentials of fungal endophytes, which would consequently increase the level of acceptance and adoption by users as an integral part of pest management programs and as a suitable alternative to chemical inputs toward sustainable crop production.

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“…The gene cluster of fumosorinone biosynthesis includes a hybrid polyketide synthase–nonribosomal peptide synthetase gene, two cytochrome P450 enzyme genes, a trans-enoyl reductase gene, and other two transcription regulatory genes [ 42 ]. Fumosorinone ( 10 ) also showed cytotoxic against human cancer lines, including HeLa, MDA-MB-231, and MDA-MB-453 cell lines [ 43 ]. A compound similar to fumosorinone, fumosorinone A ( 11 ) ( Table 1 , Figure 1 ), was identified as well.…”

Section: Secondary Metabolites (Sms) From Isaria Fumosormentioning

confidence: 99%

Secondary Metabolites and the Risks of Isaria fumosorosea and Isaria farinosa

et al. 2019

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Isaria fumosorosea and Isaria farinosa are important entomopathogenic fungi with a worldwide distribution and multiple host insects. However, the concerns about the safety risks of myco-pesticides have been attracting the attention of researchers and consumers. Secondary metabolites (SMs), especially the mycotoxins, closely affect the biosafety of Isaria myco-insecticides. In the last forty years, more than seventy SMs were identified and isolated from I. fumosorosea and I. farinose. The SMs of I. fumosorosea include the mycotoxins of non-ribosomal peptides (NRPs) (beauvericin and beauverolides), terpenes (trichocaranes and fumosorinone), lactone compounds (cepharosporolides), acids (dipicolinic acid and oxalic acid), etc. Meanwhile, the NRP mycotoxins (cycloaspeptides) and the terpene compounds (farinosones and militarinones) are the main SMs in I. farinosa. Although several researches reported the two Isaria have promised biosafety, the bioactivities and the safety risks of their SMs have not been studied in detail so far. However, based on existing knowledge, most SMs (i.e., mycotoxins) do not come from Isaria myco-insecticide itself, but are from the host insects infected by Isaria fungi, because only the hosts can provide the conditions for fungal proliferation. Furthermore, the SMs from Isaria fungi have a very limited possibility of entering into environments because many SMs are decomposed in insect cadavers. The biosafety of Isaria myco-insecticides and their SMs/mycotoxins are being monitored. Of course, SMs safety risks of Isaria myco-insecticides need further research.

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Cytotoxic activity of Shp2 inhibitor fumosorinone in human cancer cells

Cited by 6 publications

References 38 publications

A multifunctional cross-validation high-throughput screening protocol enabling the discovery of new SHP2 inhibitors

A multifunctional cross-validation high-throughput screening protocol enabling the discovery of new SHP2 inhibitors

Model Application of Entomopathogenic Fungi as Alternatives to Chemical Pesticides: Prospects, Challenges, and Insights for Next-Generation Sustainable Agriculture

Secondary Metabolites and the Risks of Isaria fumosorosea and Isaria farinosa

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