Abstract
Natural products have continued to offer tremendous opportunities for drug development, as they have long been used in traditional medicinal systems. SHP2 has served as an anticancer target. To identify novel SHP2 inhibitors with potential anticancer activity, we screened a library containing 658 natural products. Polyphyllin D was found to selectively inhibit SHP2 over SHP1, whereas two other identified compounds (echinocystic acid and oleanolic acid) demonstrated dual SHP1 and SHP2 inhibition. In a cell-based assay, polyphyllin D exhibited cytotoxicity in Jurkat cells, an acute lymphoma leukemia cell line, whereas the other two compounds were ineffective. Polyphyllin D also decreased the level of phosphorylated extracellular signal-regulated kinase (p-ERK), a proliferation marker in Jurkat cells. Furthermore, knockdown of protein tyrosine phosphatase (PTP)N6 (SHP1) or PTPN11 (SHP2) decreased p-ERK levels. However, concurrent knockdown of PTPN6 and PTPN11 in Jurkat cells recovered p-ERK levels. These results demonstrated that polyphyllin D has potential anticancer activity, which can be attributed to its selective inhibition of SHP2 over SHP1.
Highlights
Reversible protein tyrosine phosphorylation is critical in various cell signaling pathways
PTPN11 (Gene ID: 5781) encoding human SHP2 3 of 10 with several extra amino acids were cloned into the MBPpET 28a (+) vector, which was successfully used to overexpress protein tyrosine phosphatase (PTP) with enhanced solubility in an Escherichia coli expression system [24]
We identified polyphyllin D as a potent selective SHP2 inhibitor
Summary
Reversible protein tyrosine phosphorylation is critical in various cell signaling pathways. Growth factor receptor bound protein 2 (GRB2)-associated binding protein 1 (GAB1) activates SHP2 through its binding to N-SH2, thereby inactivating RasGAP, resulting in Ras activation [5,7] This leads to tumorigenesis, growth, survival, and metastasis of cells. SHP2 through its binding to N-SH2, thereby inactivating RasGAP, resulting in Ras activation [5,7] This leads to tumorigenesis, growth, survival, and metastasis of cells via the vaicatitvhaetiaocntiovfattihoenRoaf ft/hMeERKa/fE/RMKEKpa/tEhRwKaypa[8th].wInaya[d8d].itIinona,dcdointidonit,iocnoanldkitnioonckaol uknt oecxkpoeuritemxepnetrsimofeSnHtsPo2f aSlHlePle2sahlalevleesdheamvoendsetrmatoendstthraatteidt itshaaltsiot eisssaelnsotiaelssfoenr tEiarbl Bfo2riEnrdbuBc2edintduumcoedrtiugemnoersiigse[n9]e.sTish[e9]t.yTrohseintyerpohsionsepphhatoasspehSaHtaPse SinHhPib2itiinohnibaintidonknanocdkkonuot ciknocuotloinreccotalol rceacrtcailcnaormcianoHmCaTH-1C16T-c1e1ll6scperllosmporotems ogtreoswgtrhowinthviitnrovaitsrowaesllwaselilnavs iivnov, isvuog,gseusgtignegsttihnagttthhaet ltohses loofssSHofPS2HaPc2tivacittyivpitryopmromtesottehsethgerogwrotwh tohfoHf HCTC-T1-11616ceclellsls[1[100].].HHeennccee,,iinnhhiibbiittiioonn of SHHPP22 may rreessuultlstsininopoppopsoinsignsgcesnceanriaorsi.oAs.sAshsoswhnowinnbrineasbtrceanstcecramncoedreml [o9]d,eitls[s9i]l,enitcsinsgilebnloccinksg obnloccokgsenoneceoxgperneesseioxpnraenssdiotnumanodrigtuenmeosrisig, ewnheislies,inwahicleolionreactcaollocarencctearl mcaondcelr [m10o]dleolss[1o0f] SloHssPo2faScHtivPi2tyacptirvoimtyopterosmgrootewstghrowf ctohlofreccotlaolrceactraclincoarmcian.oTmhau.sT,hitus,eietmsesetmhastththatetrhoeleroolef. CChheemmiiccaallssttrruuccttuurreessooffrereppreresesenntatatitviveeSHSHPP22inihnihbiibtoitrosr.sF.uFmuomso, Ns, SNCS-8C7-8778,7I7I,BI-I0B8-,0a8n, dand GGSS--449933 aarree aaccttiivvee ssiittee iinnhhiibbiittoorrss,, wwhheerreeaassSSHHPP009999aannddppoollyypphhyylllliinnDDaarreeaalllloosstteerriicciinnhhiibbiittoorrss This motivated us to iinnvveestigate nnatural proodduuccttss wwiitthh SSHHPP22 sseelleeccttiivviittyy aass ppootteennttiiaall anticancer agents, which represents a continuation of our llaabboratory efforts ttoo iiddeennttiiffyy naturraallpprroodduucctt--ddeerriviveeddddruruggssfofrovr avraioriuosudsidseisaesaese[s22[2,223,2].3H]. This motivated us to iinnvveestigate nnatural proodduuccttss wwiitthh SSHHPP22 sseelleeccttiivviittyy aass ppootteennttiiaall anticancer agents, which represents a continuation of our llaabboratory efforts ttoo iiddeennttiiffyy naturraallpprroodduucctt--ddeerriviveeddddruruggssfofrovr avraioriuosudsidseisaesaese[s22[2,223,2].3H]. eHreeirne,iwn,ewscerescerneeedn6e5d86n5a8tunraatlpuroadl purcotsdaugcatsinasgtaninonst-rneocnep-rteocre-tpytpoer-PtyTpPesPtoTPidsetnotidtyenteiwty SnHewP2SsHelPe2ctsievleecintihviebintohrisb.itors
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