TOSK, INC. — Department of Health and Human Services SBIR Phase II: 102

Description

Principal InvestigatorGarlandWAABSTRACT SUMMARYkRASisaGTPasewhichisthemainmediatoron offofdownstreamsignalingfromtheEGFreceptorEGF Ron the surface of cellskRAS controls major signaling systems such as the RAF MEKERKcellproliferationpathwayandthePI K AKT mTORcellsurvivalpathwaySomatickRASmutationstermed oncogenic kRASare common in many cancersincidence in pancreaticin colorectalandinlungcancerMutatedkRASallowstheEGF Rsystemtobypassitsnaturalcontrolsandoperate nearly continuously in a pro growth modeWild type kRAS is self inactivatingwhile oncogenickRAS is notConsistent with this mechanismthe presence of GV mutated kRAS blocks the efficacy ofmonoclonalantibodydrugsagainstEGF RsuchaspanitumumabVectibixandcetuximabErbituxwhich are used to treat colorectal cancerhead and neckand other cancersTosk sPhaseISBIRresearchusedaproprietarygeneticallymodifiedDrosophilamelanogasterstrainthatexpressesGVkRASinitswingstoidentifytwochemicalscaffoldshitsthatsuppresskRASrelatedactivityInadditiontophenotypereversalofanti GVactivityinthemutantflythehitsweretested in relevant cell cultureprotein kinasecomputational active site dockingRAFand SOS pull downassaysAssessment of ERK activityxenograft model studiesand short term safety and PK studies werealsoperformedInformationaboutthepresencelocationandactivityofthemutantkRASgenewasalsoobtainedTherepeatabilityandreproducibilityoftheGVflyscreenswereevaluatedandconfirmedAlthough not conclusiveMOA studiesincluding knockout studies in the GV expressing flystronglysuggestthatthehitsinhibitkRASactivityintheRAS RAF MEK ERKpathwayComputationaldockingstudiesfurthersuggestadirectinteractionofthehitswithkRASpossiblyleadingtointerference with the kRAS RAF protein protein interactionTheprimarygoalsofthisPhaseIISBIRapplicationaretoperformadditionalscreeningusinganimprovedversionofthePhaseIflyassaytodiscovernewkRASinhibitorsoptimizeandfurthercharacterize the two inhibitors discovered in the SBIR Phase I and any newly discovered inhibitors fromPhase IIanduse mechanismefficacysafetyand pharmacokinetic studies to select a candidate andoneback up ready for IND enabling tests needed to file an IND for an inhibitor of mutant kRAS