Triple negative breast cancers (TNBC) have the worst prognoses of human breast cancers. A factor in this poor outcome is the lack of targeted therapies. Major target receptors are absent (ER, PR) or not amplified (HER-2/neu). Cytotoxic chemotherapy persists as the primary systemic treatment option for TNBC patients, and has life-threatening toxicities such bleeding, and kidney and heart damage. Although the recent approval of atezolizumab in combination with nab-paclitaxel is a seminal event, anti-PD-L1 immunotherapy has achieved only modest response rates in TNBC patients. Inhibition of downstream PI3K effectors, such as AKT, has been clinically validated as a treatment modality but therapeutic windows are small. Resistance to AKT inhibitors such as capivasertib has also been observed in TNBC cell lines. Recent studies have shown serum and glucocorticoid-regulated kinase 1 (SGK1) to be a novel target for treatment of TNBC. SGK1 is an anti- apoptotic kinase that drives proliferation and metastasis of TNBC tumors and is not expressed at detectable levels in normal breast tissue. In particular, SGK1 is overexpressed in the Mesenchymal Stem cell-Like (MSL) subtype of TNBC, which accounts for 20% of TNBC tumors. MSL tumors are also classified as claudin-low, and MSL/claudin-low tumors have one of the poorest prognoses among TNBC subtypes for overall survival and metastasis-free survival. Preclinical studies have shown that SGK1 knockdown or pharmacological inhibition of SGK1 (our own preliminary data) impairs proliferation and metastasis of claudin-low TNBC cells. Additional evidence shows that TNBC cells rely on SGK1 to evade death induced by AKT inhibitors. A major difficulty in treating TNBCs arises from the heterogeneity of these tumors, leading to variable treatment outcomes. We hypothesize that dual specificity inhibition of both SGK1 and AKT1 can provide a novel targeted therapy for claudin-low TNBC. Inhibitors of SGK1 previously discovered for other indications are unsuitable for clinical development in combination with AKT inhibitors due to weak cellular potency and inadequate drug-like properties. Using the innovative Leap-to-Lead⢠technology, we have identified a novel series of dual SGK1/AKT1 inhibitors with cellular potency derived from superior drug-like properties. In this Phase I SBIR, we will optimize the potency, selectivity, and ADME properties of our lead series using structure-guided chemistry (applying our innovative Leap-to-Lead⢠and BindingSIGHTs design platforms) and a property-driven medicinal chemistry approach. The newly generated analogs will then progress through functional cell assays, kinase selectivity panels, ADME and pharmacokinetic (PK) experiments to select compounds for in vivo evaluation. Finally, we will examine the efficacy of 1-2 lead compounds in a xenograft model of human TNBC. Successful 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.
Public Health Relevance Statement: PROJECT NARRATIVE Triple negative breast cancer (TNBC) is one of the deadliest subtypes of breast cancer and causes a disproportionate share of the nearly 40,000 breast cancer deaths each year in the United States. Tragically, TNBC tends to strike younger victims in the prime of their life, occur more often in African- American and Hispanic women, and metastasize early in the course of the disease. This project will demonstrate proof-of-concept that dual specificity inhibitors of serum and glucocorticoid-regulated kinase 1 (SGK1) and AKT1 can provide a targeted therapy for TNBC by showing efficacy in an orthotopic xenograft model of human breast cancer.
Project Terms: African American; AKT inhibition; AKT1 gene; analog; Animal Model; anti-cancer; anti-PD-L1; Apoptosis; Apoptotic; base; Binding Proteins; Biological Assay; Biological Availability; Biological Markers; Breast; Breast Cancer Cell; Breast Cancer cell line; Breast Cancer Patient; Breast Cancer Treatment; Cancer Etiology; cancer subtypes; Cell Membrane Permeability; Cells; Cellular Assay; Cessation of life; Chemistry; Clinical; clinical development; computational platform; Critical Pathways; Cytochrome P450; Cytotoxic Chemotherapy; Data; design; Development; Disease; Drug Kinetics; efficacy study; ERBB2 gene; Event; Exhibits; experimental study; Formulation; FRAP1 gene; Goals; Growth; heart damage; Hemorrhage; Hispanics; Human; Human Cell Line; human model; Immunotherapy; Impairment; In Vitro; in vivo; in vivo evaluation; inhibitor/antagonist; innovation; kinase inhibitor; Kinetics; knock-down; Lead; lead candidate; lead optimization; lead series; Life; Liver Microsomes; Lupus erythematosus cell; malignant breast neoplasm; Mammary Gland Parenchyma; MDA MB 231; meetings; men; Mesenchymal Stem Cells; Metabolism; Methods; Modality; Molecular Weight; mortality; Mus; Neoplasm Metastasis; new therapeutic target; novel; novel strategies; Outcome; overexpression; Paclitaxel; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacology and Toxicology; Phase; Phosphotransferases; preclinical development; preclinical study; Property; Protein Isoforms; Proto-Oncogene Proteins c-akt; receptor; renal damage; Reporting; Research; Resistance; response; scale up; Schedule; Seminal; Series; Sgk protein; Signal Transduction; Small Business Innovation Research Grant; Solubility; Specificity; standard of care; stem-like cell; Structure; targeted treatment; Technology; Therapeutic; tool; Toxic effect; Treatment Efficacy; Treatment outcome; triple-negative invasive breast carcinoma; tumor; tumor heterogeneity; tumor xenograft; United States; Woman; Xenograft Model; Xenograft proced
