Small molecule Inhibitors of steroid receptor coactivator to treat breast cancer

ABSTRACTSteroid Receptor CoactivatorSRCis a key breast cancer oncogene that is frequently overexpressed or amplified in estrogen receptorERand human epidermal growth factor receptorHERpositive breast cancersElevated expression of SRCalso has been associated with resistance to tamoxifen therapy and with poor disease outcome in HERpositive breast cancersNumerous studies have shown that experimental targeting of SRCcan limit breast cancer cell growth and restore the anti estrogenic actions of tamoxifenSRChas been well characterized and murine proof of concept studies suggest inhibition of this target will lead to an entirely new class of drugs for a wide range of SRC overexpressing tumorsSRCs are a promising target since they function as coactivators not only for nuclear receptors like ERbut also as key coactivators for `growth promotingandapostranscription factors such as such as E FTwistNfkappaB and othersThese transcription factors are lucrative targets for difficult to treat tumors such as triple negative breast cancerTNBCand hormone refractory breast cancerMost targeted therapeutic drugs available are designed to inhibit only one pathwayHoweverdrug resistance often occurs when tumors shift to alternative growth pathwaysrendering the original targeted pathway non essential for tumor growthInhibiting SRChas implications on multiple relevant cancer signaling pathways simultaneouslyand accordingly it is an ideal target for difficult to treat cancersWe have identified proprietary small molecules that selectively and potently inhibit SRCprotein levelsWe have demonstrated that these inhibitors prevent TNBC tumor growth in vivo and effectively kill cancer stem cellsIn our preliminary studieswe elucidated the metabolic mechanisms of these inhibitors and developed proprietary derivatives with improved drug like properties resulting in our current lead molecule SIDuring this PhaseSTTRinspired by our encouraging preliminary study showing that TNBC cell lines with subtypes involving growth factor signaling pathways are more sensitive to SRCinhibition induced toxicitywe will determine the ICvalues of SIin all the TNBC cell lines in the ATCC Breast Cancer Cell PanelATCCKand correlate the ICvalues with the TNBC subtypesWe will also measure the SRClevels in these TNBC cell lines using Western blot with and without SItreatmentWe will compare whether a high protein level of SRCin TNBC cell lines is correlated with SIsensitivity and evaluate the ability of SIto block TNBC tumor growth in vivoIn a subset of SIsensitive TNBC cellswe will also determine the changes of cell migration and invasion abilities upon SItreatmentWe will then extensively characterize SIfor the shelf stabilityin vitro and in vivo ADMET profilesproteomics based target identificationtranscriptome wide RNA sequencing and PKPD relationshipDuring Phase II SIwill be evaluated in patient derived xenograft breast cancer models representing TNBC tumors and conduct extensive IND enabling evaluations of SIandapos s biodistributionpharmacokinetics and toxicity Project NarrativeThere is an urgent need to identify new targets and to develop new therapeutics to inhibit metastasis and in combination with standard of care to improve triple negative breast cancer managementOur novel class of proprietary Steroid Receptor CoactivatorSRCinhibitor small molecules has been shown to limit Triple Negative Breast CancerTNBCcell growth in vitro and in vivoSRChas been well characterized and murine proof of concept studies suggest inhibition of this target will lead to an entirely new class of drugs for a wide range of SRC overexpressing tumors including TNBC