Dual Modulators of p53 and Cyclin D in ER Alpha Signaling by Albumin Nanovectors Bearing Zinc Chaperones for ER-positive Breast Cancer Therapy

Abstract

Abstract:: The inherited mutations and underexpression of BRCA1 in sporadic breast cancers results in the loss or functional inactivation of BRCA1 may contribute to high risk to breast cancer. Recent researchers have identified small molecules (BRCA1 mimetics) that fit into a BRCA1 binding pocket within Estrogen Receptor alpha (ERα), mimic the ability of BRCA1 to inhibit ERα activity, and overcome antiestrogen resistance. Studies indicate that most of the BRCA1 breast cancer cases are associated with p53 mutations. It indicates that there is a potential connection between the BRCA1 and p53. Most p53 mutations are missense point mutations that occur in the DNA-binding domain. Structural studies have demonstrated that mutant p53 core domain misfolding especially p53-R175H is reversible. Mutant p53 reactivation with a new class of zinc metallochaperones (ZMC) that restore WT p53 structure and function by restoring Zn2+ to Zn2+ deficient mutant p53. Considering the role of WT BRCA1 and reactivation of p53 in tumor cells our hypothesis is to target the both tumor suppressor proteins by a novel biomolecule (ZMC). Since both proteins are present in the same cell and functionally inactive, state may be a novel efficacious therapeutic regime for breast cancer therapy. In addition, we propose to use Albumin Nanovector (ANV) formulation for target drug release.

Design and Synthesis of Novel Benzoazepinone Derivatives as Potent Estrogen Receptor Alpha Inhibitors

“…After completion of the reaction, it was cooled to 0-5°C and quenched with ice and 1N HCl solution. The organic portion was separated [31] . The organic layer was extracted with DCM (2X500 mL), the combined organic layer washed with 1N HCl (200 mL) and then saturated sodium bicarbonate solution (200 mL).…”