Development of dual inhibitors of the kinases SGK1 and AKT1 for blockade of a critical pathway in triple-negative breast cancer

ABSTRACTTriple negative breast cancersTNBChave the worst prognoses of human breast cancersA factor in this poor outcome is the lack of targeted therapiesMajor target receptors are absentERPRor not amplifiedHERneuCytotoxic chemotherapy persists as the primary systemic treatment option for TNBC patientsand has life threatening toxicities such bleedingand kidney and heart damageAlthough the recent approval of atezolizumab in combination with nab paclitaxel is a seminal eventanti PD Limmunotherapy has achieved only modest response rates in TNBC patientsInhibition of downstream PI K effectorssuch as AKThas been clinically validated as a treatment modality but therapeutic windows are smallResistance to AKT inhibitors such as capivasertib has also been observed in TNBC cell linesRecent studies have shown serum and glucocorticoid regulated kinaseSGKto be a novel target for treatment of TNBCSGKis an antiapoptotic kinase that drives proliferation and metastasis of TNBC tumors and is not expressed at detectable levels in normal breast tissueIn particularSGKis overexpressed in the Mesenchymal Stem cell LikeMSLsubtype of TNBCwhich accounts forof TNBC tumorsMSL tumors are also classified as claudin lowand MSL claudin low tumors have one of the poorest prognoses among TNBC subtypes for overall survival and metastasis free survivalPreclinical studies have shown that SGKknockdown or pharmacological inhibition of SGKour own preliminary dataimpairs proliferation and metastasis of claudin low TNBC cellsAdditional evidence shows that TNBC cells rely on SGKto evade death induced by AKT inhibitorsA major difficulty in treating TNBCs arises from the heterogeneity of these tumorsleading to variable treatment outcomesWe hypothesize that dual specificity inhibition of both SGKand AKTcan provide a novel targeted therapy for claudin low TNBCInhibitors of SGKpreviously discovered for other indications are unsuitable for clinical development in combination with AKT inhibitors due to weak cellular potency and inadequate drug like propertiesUsing the innovative Leap to Leadtechnologywe have identified a novel series of dual SGKAKTinhibitors with cellular potency derived from superior drug like propertiesIn this Phase I SBIRwe will optimize the potencyselectivityand ADME properties of our lead series using structure guided chemistryapplying our innovative Leap to Leadand BindingSIGHTs design platformsand a property driven medicinal chemistry approachThe newly generated analogs will then progress through functional cell assayskinase selectivity panelsADME and pharmacokineticPKexperiments to select compounds for in vivo evaluationFinallywe will examine the efficacy oflead compounds in a xenograft model of human TNBCSuccessful completion of the Phase I SBIR milestones will justify preclinical development of the lead series in Phase II SBIR studies with the goals of optimizing in vivo efficacy in animal models of human TNBC and determining pharmacology and toxicology profiles to select a lead candidate for IND enabling studies PROJECT NARRATIVE Triple negative breast cancerTNBCis one of the deadliest subtypes of breast cancer and causes a disproportionate share of the nearlybreast cancer deaths each year in the United StatesTragicallyTNBC tends to strike younger victims in the prime of their lifeoccur more often in AfricanAmerican and Hispanic womenand metastasize early in the course of the diseaseThis project will demonstrate proof of concept that dual specificity inhibitors of serum and glucocorticoid regulated kinaseSGKand AKTcan provide a targeted therapy for TNBC by showing efficacy in an orthotopic xenograft model of human breast cancer