Design and synthesis of EGFR dimerization inhibitors and evaluation of their potential in the treatment of psoriasis

Petch, Donna; Anderson, Rosaleen J.; Cunningham, Anne; George, Suja E.; Hibbs, David E.; Liu, Ran; Mackay, Simon P.; Paul, Andrew; Small, David A.; Groundwater, Paul W.

doi:10.1016/j.bmc.2012.07.048

Cited by 19 publications

(12 citation statements)

References 54 publications

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“…The gel filtration profiles and enzymatic activities of these mutants clearly explain the reason why Est22 has hyperthermostability and very high enzymatic activity. Notably, disruption of dimerization has successfully been employed as a strategy for the development of effective inhibitors2223.…”

Section: Resultsmentioning

confidence: 99%

Structural insights of a hormone sensitive lipase homologue Est22

Huang

Huo

et al. 2016

Sci Rep

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Hormone sensitive lipase (HSL) catalyzes the hydrolysis of triacylglycerols into fatty acids and glycerol, thus playing key roles in energy homeostasis. However, the application of HSL serving as a pharmaceutical target and an industrial biocatalyst is largely hampered due to the lack of high-resolution structural information. Here we report biochemical properties and crystal structures of a novel HSL homologue esterase Est22 from a deep-sea metagenomic library. Est22 prefers short acyl chain esters and has a very high activity with substrate p-nitrophenyl butyrate. The crystal structures of wild type and mutated Est22 with its product p-nitrophenol are solved with resolutions ranging from 1.4 Å to 2.43 Å. The Est22 exhibits a α/β-hydrolase fold consisting with a catalytic domain and a substrate-recognizing cap domain. Residues Ser188, Asp287, and His317 comprise the catalytic triad in the catalytic domain. The p-nitrophenol molecule occupies the substrate binding pocket and forms hydrogen bonds with adjacent residues Gly108, Gly109, and Gly189. Est22 exhibits a dimeric form in solution, whereas mutants D287A and H317A change to polymeric form, which totally abolished its enzymatic activities. Our study provides insights into the catalytic mechanism of HSL family esterase and facilitates the understanding for further industrial and biotechnological applications of esterases.

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Section: Resultsmentioning

confidence: 99%

Structural insights of a hormone sensitive lipase homologue Est22

Huang

Huo

et al. 2016

Sci Rep

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“…As shown recently by Hsieh et al ., activation of EGFRs in psoriatic lesions can be inhibited by indirubin and thus ameliorate epidermal keratinocyte proliferation. Recently described cases of successful treatment with EGFR inhibition resulting in complete resolution of psoriatic lesions has encouraged research into new EGFR inhibitors designed exclusively for the treatment of psoriasis …”

Section: Discussionmentioning

confidence: 99%

“…Recently described cases of successful treatment with EGFR inhibition resulting in complete resolution of psoriatic lesions has encouraged research into new EGFR inhibitors designed exclusively for the treatment of psoriasis. [18][19][20]…”

Section: Discussionmentioning

confidence: 99%

Effect of psoriasis activity on epidermal growth factor (EGF) and the concentration of soluble EGF receptor in serum and plaque scales

et al. 2014

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“…The requirement of dimerization for the function and stability of HSL-family enzymes focuses attention on the dimeric interface as a potential target for structure-aided drug design. Notably, disruption of dimerization has successfully been employed as a strategy for the development of effective inhibitors (Petch et al, 2012;Zhao et al, 2010).…”

Section: Dimeric Interfacementioning

confidence: 99%

Structural and functional analyses of a bacterial homologue of hormone-sensitive lipase from a metagenomic library

Ngo

Ryu

et al. 2013

Acta Crystallogr D Biol Cryst

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Intracellular mobilization of fatty acids from triacylglycerols in mammalian adipose tissues proceeds through a series of lipolytic reactions. Among the enzymes involved, hormone-sensitive lipase (HSL) is noteworthy for its central role in energy homeostasis and the pathogenic role played by its dysregulation. By virtue of its broad substrate specificity, HSL may also serve as an industrial biocatalyst. In a previous report, Est25, a bacterial homologue of HSL, was identified from a metagenomic library by functional screening. Here, the crystal structure of Est25 is reported at 1.49 Å resolution; it exhibits an α/β-hydrolase fold consisting of a central β-sheet enclosed by α-helices on both sides. The structural features of the cap domain, the substrate-binding pocket and the dimeric interface of Est25, together with biochemical and biophysical studies including native PAGE, mass spectrometry, dynamic light scattering, gel filtration and enzyme assays, could provide a basis for understanding the properties and regulation of hormone-sensitive lipase (HSL). The increased stability of cross-linked Est25 aggregates (CLEA-Est25) and their potential for extensive reuse support the application of this preparation as a biocatalyst in biotransformation processes.

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Design and synthesis of EGFR dimerization inhibitors and evaluation of their potential in the treatment of psoriasis

Cited by 19 publications

References 54 publications

Structural insights of a hormone sensitive lipase homologue Est22

Structural insights of a hormone sensitive lipase homologue Est22

Effect of psoriasis activity on epidermal growth factor (EGF) and the concentration of soluble EGF receptor in serum and plaque scales

Structural and functional analyses of a bacterial homologue of hormone-sensitive lipase from a metagenomic library

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