A New Small-Molecule Kinase Inhibitor for Breast Cancer

NuPeak Therapeutics Incis a biotechnology start up companyC corporationdesigned to deliver a first inclass small molecule kinase inhibitorThe present Project is aimed at an inhibitor for treatment of breast cancerwhich remains a leading cause of morbidity and mortality in the U Sdespite current therapeutic approachesIn that contextwe identified a novel typeimmune response that activates mitogen activated protein kinaseMAPKto drive epithelial progenitor stem cell metaplasia in the airwayWe reasoned that the findings might be relevant to reports of typeimmune activation and MAPKfunction in carcinomasIn particularMAPKexpression correlates with decreased survival in breast cancerand MAPKgene knockdown and knockout attenuates breast cancer cell growth in vitro and in vivoMoreoverMAPKfunction was independent of estrogen receptorERprogesterone receptorPRor ERBBHERstatussuggesting relevance to ER PRHERnegativetriple negativebreast cancersHoweverto our knowledgethere were no MAPKinhibitors available to test this applicationIn that regardwe obtained the first x ray crystal structure of MAPKand used structure based drug design to develop the first small molecule inhibitors of MAPKWe since performed additional medicinal chemistry to generate proprietary chemical analogs that show marked increases in potency and selectivity and form the basis for approved and pending patentsOur Preliminary Studies show that these new inhibitors block proliferation of luminal hormone receptor positive and basal like triple negative breast cancer cells in culture and identify a lead compound that inhibits cell growth at concentrationsGInMthat are nontoxic and compare favorably with approved kinase inhibitorsThis lead also demonstrates favorable results from MAPKenzyme assayICnMkinase selectivity assaysphysical chemical property assessmentsADMET microsomal stability and cell permeability assaysand pharmacokineticPKanalysis for oral dosing in vivoThuswe propose a Phase I STTR program for investigators at NuPeak and Washington University to advance this lead through Specific Aims that evaluate the lead in controlling breast cancer cell lines in cell cultureAimand after subcutaneous xenotransplantation or intravenous injection of these cell lines in miceAimNuPeak will operate with the entrepreneurial resources of BioGenerator St Louis and CORTEX biotech district and a quick license from Washington University under patents for the lead and related proprietary compoundsThe commercialization strategy will be based on establishing initial efficacy and nontoxicity of a lead compound in relation to MAPKexpression and activation in PhaseSTTR studiesfurther development towards IND status and initial safety clinical trials in PhaseSTTR studiesand then more advanced clinical trials and FDA approval in partnership with the pharmaceutical industryThuswe expect PhaseSTTR to provide the basis for pursuit of additional data in Phaseaimed at GMP protocolsfurther non GLP and GLP safety and toxicity studiesand Phase I IIA clinical trials of a first in class MAPKinhibitor in humans Relevance Cancer is a leading cause of morbidity and mortality in the U Sdespite current therapeutic approachesIn particularinvasive breast cancer cases develop atper year and result indeaths forThe proposed development of a new anti cancer drug that is safe and effective will thereby address an unmet need for a major public health problem