Figure 4.

Increasing MPA’s brain penetrance enhances its anti-BM phenotype in vivo

(A) Summary of the design and synthesis strategy for MPA analogs. See supplementary information for chemical syntheses.

(B) A summary of each analog’s activity following dose-response assays. N/A, not applicable.

(C) Dose-response curves of a lung-BMIC line (BT478), breast-BMIC line (MDA-MB-231 Br), melanoma-BMIC line (BT673), and neural stem control cells following a 72-h treatment with MPA or Compound 3. PrestoBlue readout is normalized to vehicle-treated cells and data are presented as mean ± SD from 4 technical replicates.

(D) Brain penetrance was evaluated in vitro using the parallel artificial membrane permeability (PAMPA) assay. Permeability coefficients (−LogP_e) > 6 indicate low CNS permeability, whereas −LogP_e < 6 indicate high CNS permeability. Caffeine was used as a BBB-permeable control. Comparisons were made via a two-tailed unpaired t test and data are presented as mean ± SD from 3 technical replicates. p value is indicated.

(E) Schematic of treatment regimen. Mice were treated daily by oral gavage using either MPA, Compound 3, or placebo.

(F) Kaplan-Meier survival analysis of control-, MPA-, and Compound 3-treated mice. Log rank test, p value is indicated (n.s., not significant [MPA], ∗∗∗p = 0.0005 [Compound 3]).