LY-3039478 is an orally bioavailable, novel small molecule inhibitor of Notch signaling pathway, developed Eli Lilly and Company for cancer treatment. The Notch receptor, on the surfaces of progenitor cells and cancer cells, binds neighboring cell-surface ligands DLL or JAGGED. On ligand binding, the intramembrane protease γ-secretase cleaves the Notch intracellular domain (NICD). LY-3039478 is an exquisitely potent inhibitor of Notch-1 intracellular domain (N1ICD) cleavage with an IC50 of ∼1nM in most of the tumor cell lines tested. LY3039478 also potently inhibits mutant Notch receptor activity. Treatment with a gamma-secretase inhibitor, LY3039478, significantly inhibited the growth of 2 CCRCC(Clear cell renal cell carcinoma) cell lines in a concentration-dependent manner. LY3039478 treatment also led to decreased expression of Myc and Cyclin A1, two genes that were part of the NOTCH driven proliferative signature in murine and human model systems. LY3039478 treatment also led to G0/G1 cell cycle arrest in CCRCC cells. In a xenograft tumor model, LY3039478 inhibited N1ICD cleavage and expression of Notch-regulated genes in the tumor microenvironment. The inhibition of Notch cleavage also resulted in the induction of apoptosis in a Notch-dependent xenograft model. In immunodeficient NSG mice xenografted with 769-P CCRCC cells, LY3039478 treatment resulted in significantly increased survival and delayed tumor growth in independent cohorts of mice demonstrating in vivo efficacy in CCRCC. LY3039478 is being investigated in a clinical trial in patients with T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma in combination with Dexamethasone.