Fig. 3: Dynamics of BRD-810-induced killing suggests a short-term 1-h coverage of unbound IC50 sufficient to induce antitumor efficacy in vivo.
a, Cancer cells were exposed to increasing concentrations of BRD-810 for 5 min, 1 h, 3 h or 6 h before the compound was washed off and replaced by medium or cancer cells were continuously exposed for 24 h. Antiproliferative IC50 values were determined at 24 h and corrected for the free fraction of BRD-810 in the cell culture medium to get the IC50u. Data are shown as individual measurements of independently performed experiments (n = 7 cell lines per time point). b, BRD-810 plasma concentrations in blood from immunocompromised mice that were intravenously injected with BRD-810. The solid line indicates the modeled exposure data based on a mouse-PK model; the dashed line indicates the in vitro antiproliferative IC50u of BRD-810 in MOLP-8 cells. c, BRD-810 was intravenously injected into MOLP-8 tumor-xenografted mice. Tumors were sampled at the indicated time points and the total caspase 3 and cleaved caspase 3 levels were measured by western blot using human-specific antibodies and subsequently quantified by densiometric analysis. Data are shown as the median and quartiles (n = 3 tumors per dose and time point). d,e, Antitumor efficacy (d) and body weight (e) of MOLP-8 tumor-xenografted mice (n = 10 mice per group) after once-weekly intravenous injections of BRD-810. Data are shown as the mean and s.d.
