#92 A new class of BRCA-1 mimetics for ER positive breast cancer therapy: Design, synthesis and in-vitro screening

Abstract

Inherited mutations of the breast cancer susceptibility gene BRCA1 and the frequent (30-40%) underexpression of BRCA1 in sporadic breast cancers and 46% of sporadic breast cancers show loss of one BRCA1 allele. These findings suggest that loss or functional inactivation of BRCA1 may contribute to this larger group of cancers. This study aims to find a novel class of BRCA1 mimics for Estrogen Receptor α (ERα) breast cancer that works differently from conventional antiestrogens. A novel class of hybrids with coumarin and thiosemicarbazone scaffolds was created with the premise of developing small compounds that imitate the function of BRCA-1 to regulate the ER down and inhibit the tumor activity of breast cancer cells. Using Schrodinger 2020-2, ADMET and in-silico molecular docking tests of the proposed hybrids were performed on the BRCA-1 binding cavity of ER alpha. Coumarin Thiosemicarbazone derivatives were synthesized from 7-hydroxy-4-methylcoumarin, 4-hydroxycoumarin and thiosemicarabazide with different aldehydes. All the compounds were screened for their *in vitro* cytotoxicity activity using Vero and MDA MB 231 cell lines by MTT assay. Gene expression studies were performed for Cyclin D1 and BCL2 genes by RealTime PCR using ∆∆the Ct method. The QSAR model against MDA MB 231 cell line was obtained using the multiple linear regression method and was validated by both internal and external validation procedures. IC$_{50}$ values from Cytotoxicity studies by MTT assay ranges from 5 μg/mL to 149 μg/mL. The synthesized hybrids TSCO-VI (-0.048), TSCO-XXVII (-0.217), and XXVIII (-0.214) downregulate the CyclinD1. Similarly, the hybrids all TSCO-VI (-0.628), TSCO-XVII (-0.373), TSCO-XXVII (-0.320), and XXVIII (-0.376) down-regulated the BCL2 gene. Besides, we found RMSE value=0.27760 and Correlation Coefficient (R$^{2}$)= 0.45112 in 2D QSAR by MLR method. The cytotoxicity and gene expression study findings suggest that we have found a new class of BRCA1 mimetics that works differently from conventional antiestrogens for breast cancer therapy.

Fig. Overview of the Regulatory Interplay Between BRCA-1 and ER Alpha