Figure 5. Antipsychotics modulated SMAD3-responsive genes in brains from antipsychotic-treated patients and a subset of cell lines.

(A,B) SAR data from the SBE4-luc SMAD reporter in T6PNE (Figure 2C) correlated with the statistical association between genes altered in human brains of antipsychotic treated patients with schizophrenia and genes containing SMAD3 (A) or SMAD1 (B) binding sites in their promoters. Data from Mudge et al.¹¹ are in black and data from Narayan et al.¹² are in green. For A, correlation coefficient=0.89 (p=0.0013) and for B, correlation coefficient=0.42 (p=0.24). (C–E) The same analysis used in A and B was performed on data from the Broad Connectivity Map (CMAP 2.0) compound database⁴⁸. The SBE4 reporter SAR (Figure 5C) was correlated with SMAD3 responsiveness in PC3 cells (correlation coefficient=.88, p=0.00036)(C), but not MCF7 cells (correlation coefficient=−0.10, p=0.75) (D) or HL-60 cells (correlation coefficient=.22, p=0.47)(E). (F) Ethopropazine increased activity on the SMAD2/3 responsive SBE4-luc reporter in PC3, LU1205, and T6PNE, but not MCF7, WM35, HepG2, H157, Panc-1, and Hela cells. (n≥3), Error bars are SEM. * indicates p<0.05 relative to DMSO control.