UM-164 (Synonyms: DAS-DFGO-II)

UM-164 is a highly potent inhibitor of c-Src with a Kd of 2.7 nM. UM-164 also potently inhibits p38α and p38β.

In biochemical assays, UM-164 is a highly potent inhibitor of c-Src with a binding constant comparable with Dasatinib (UM-164 Kd=2.7 nM, Dasatinib Kd=0.7 nM). To confirm that UM-164 is capable of inhibiting the activation of c-Src in vitro, the effect of UM-164 is examined on the c-Src autophosphorylation in two TNBC cell lines (MDA-MB 231 and SUM 149). Inhibition of c-Src autophosphorylation is detected in a concentration- and a time-dependent manner. At 120 minutes, complete abrogation of c-Src autophosphorylation is observed at 50 nM, demonstrating that UM-164 is a potent c-Src inhibitor in vitro. Flow cytometry experiments demonstrate that UM-164 treatment of MDA-MB 231 and SUM 149 increased the proportion of G0-G1 cells by 25% and 28%, respectively, and concurrently decreased the fraction of S cells by 16% and 19%, respectively[1].

A xenograft study is performed using NCr/nude mice implanted with MDA-MB 231 and SUM 149 cell lines. Once the tumors become palpable, the mice are randomized into control and treatment groups. Mice are injected intraperitoneally with either drug (10 and 20 mg/kg in both xenograft studies; a 15 mg/kg dose is added to the SUM 149 xenograft studies) or vehicle every other day (n=5 for each group). At the selected doses of UM-164, there is no significant weight loss or gross abnormalities observed in the treated animals, even after 52 days of treatment. However, tumor growth is significantly inhibited in both the 10 mg/kg and 20 mg/kg dose groups compared with the vehicle-treated group (P<0.026 and P<0.004, respectively)[1].

References:
[1]. Gilani RA, et al. UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer. Clin Cancer Res. 2016 Oct 15;22(20):5087-5096.