The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study
Burslem GM, Smith BE, Lai AC, Jaime-Figueroa S, McQuaid DC, Bondeson DP, Toure M, Dong H, Qian Y, Wang J, Crew AP, Hines J, Crews CM. The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study. Cell Chemical Biology 2017, 25: 67-77.e3. PMID: 29129716, PMCID: PMC5831399, DOI: 10.1016/j.chembiol.2017.09.009.Peer-Reviewed Original ResearchConceptsReceptor tyrosine kinasesProtein familyProtein degradationTyrosine kinaseDownstream signaling responseTargeted Protein DegradationDevelopment of PROTACsTargeted degradationEndogenous proteinsSignaling responseChimera technologyCell proliferationPROTACsPROTAC technologyKinaseKinase inhibitorsLigand showAdvantages of degradationReceptor tyrosine kinase inhibitorsTyrosine kinase inhibitorsInhibitionDegradationFamilyPowerful toolProteolysisActivation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth
Sangodkar J, Perl A, Tohme R, Kiselar J, Kastrinsky D, Zaware N, Izadmehr S, Mazhar S, Wiredja D, O’Connor C, Hoon D, Dhawan N, Schlatzer D, Yao S, Leonard D, Borczuk A, Gokulrangan G, Wang L, Svenson E, Farrington C, Yuan E, Avelar R, Stachnik A, Smith B, Gidwani V, Giannini H, McQuaid D, McClinch K, Wang Z, Levine A, Sears R, Chen E, Duan Q, Datt M, Haider S, Ma’ayan A, DiFeo A, Sharma N, Galsky M, Brautigan D, Ioannou Y, Xu W, Chance M, Ohlmeyer M, Narla G. Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth. Journal Of Clinical Investigation 2017, 127: 2081-2090. PMID: 28504649, PMCID: PMC5451217, DOI: 10.1172/jci89548.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsCell Line, TumorCell SurvivalDrug Resistance, NeoplasmEnzyme ActivationEnzyme ActivatorsHumansMaleMice, Inbred BALB CMice, NudeMice, TransgenicProtein BindingProtein Phosphatase 2Proto-Oncogene Proteins p21(ras)Signal TransductionTumor BurdenXenograft Model Antitumor AssaysConceptsTumor suppressor proteinSmall molecule activatorsSuppressor proteinTumor suppressor protein phosphatase 2AMolecule activatorsProtein phosphatase 2AInactivation of kinasesOncogenic signaling proteinsPhosphatase 2AScaffold subunitSignaling proteinsEndogenous phosphatasesNegative regulatorOncogenic kinasesConformational changesCancer-associated molecular targetsKRAS-mutant lung cancerPP2AMolecular targetsProteinCancer cellsKinaseMouse xenograftsTreatment of cancerActivator