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Ref Type Journal Article
PMID (27154914)
Authors Gilani RA, Phadke S, Bao LW, Lachacz EJ, Dziubinski ML, Brandvold KR, Steffey ME, Kwarcinski FE, Graveel CR, Kidwell KM, Merajver SD, Soellner MB
Title UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 22
Issue 20
Date 2016 Oct 15
URL
Abstract Text c-Src has been shown to play a pivotal role in breast cancer progression, metastasis, and angiogenesis. In the clinic, however, the limited efficacy and high toxicity of existing c-Src inhibitors have tempered the enthusiasm for targeting c-Src. We developed a novel c-Src inhibitor (UM-164) that specifically binds the DFG-out inactive conformation of its target kinases. We hypothesized that binding the inactive kinase conformation would lead to improved pharmacologic outcomes by altering the noncatalytic functions of the targeted kinases.We have analyzed the anti-triple-negative breast cancer (TNBC) activity of UM-164 in a comprehensive manner that includes in vitro cell proliferation, migration, and invasion assays (including a novel patient-derived xenograft cell line, VARI-068), along with in vivo TNBC xenografts.We demonstrate that UM-164 binds the inactive kinase conformation of c-Src. Kinome-wide profiling of UM-164 identified that Src and p38 kinase families were potently inhibited by UM-164. We further demonstrate that dual c-Src/p38 inhibition is superior to mono-inhibition of c-Src or p38 alone. We demonstrate that UM-164 alters the cell localization of c-Src in TNBC cells. In xenograft models of TNBC, UM-164 resulted in a significant decrease of tumor growth compared with controls, with limited in vivo toxicity.In contrast with c-Src kinase inhibitors used in the clinic (1, 2), we demonstrate in vivo efficacy in xenograft models of TNBC. Our results suggest that the dual activity drug UM-164 is a promising lead compound for developing the first targeted therapeutic strategy against TNBC. Clin Cancer Res; 22(20); 5087-96. ©2016 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
UM-164 p38 MAPK Inhibitor (Pan) 4 SRC Inhibitor 29 UM-164 is a small molecule that binds to a specific inactive conformation of Src, resulting in inhibition of Src downstream signaling and inhibits p38 MAPKs, resulting in growth inhibition, and apoptosis in tumor cells (PMID: 27154914, PMID: 29282631, PMID: 28463369).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
SRC positive triple-receptor negative breast cancer predicted - sensitive UM-164 Preclinical - Cell line xenograft Actionable In a preclinical study, UM-164 inhibited proliferation and induced apoptosis in human triple-receptor negative breast cancer cell lines with elevated Src activity in culture, and inhibited tumor growth in cell line xenograft models (PMID: 27154914). 27154914
SRC positive triple-receptor negative breast cancer sensitive BIRB-796 + Dasatinib Preclinical - Cell culture Actionable In a preclinical study, BIRB-796 in combination with Sprycel (dasatinib) resulted in improved growth inhibition in both 2D and 3D cultures of triple-receptor negative breast cancer cell lines with elevated Src activity compared to single agent treatment (PMID: 27154914). 27154914