Design and Development of Novel Cyclin-Dependent Kinase Inhibitors to Treat Triple Negative Breast Cancer (TNBC)

Abstract

Breast cancer is the most common cancer in women worldwide. There are four different types of breast cancers, ER+, PR+, Her-2+ and triple-negative (TNBC). Of these, TNBC is extremely difficult to treat due to the absence of ER+, PR+, Her2+ expression and not respond to any targeted and hormonal therapies. Currently, there is no standard chemotherapeutic agent for the treatment of TNBC. The successful completion of this study would help us to develop highly safe, efficient and inexpensive therapies for the treatment of TNBC. The design of the ligands was initiated with the optimization and refining of five different CDK protein. The linkers such as flavone and hydantoin were used with different substitutions. The protein was first prepared using the Protein Preparation wizard, and the docking studies were performed using the Schrodinger Glide software (Maestro 9.5) with extra-precision (XP) mode. The glide energy of the ligands was used to select the best fit molecules by the high binding affinity and selectivity towards AR. ADME properties and DFT calculation were utilized for the analysis of best-fit molecules. Based on the computational results, the best fit molecules were selected for the synthesis. Taking into account the interesting properties of these derivatives, a series of novel ligands were synthesized by using conventional methods. Most of the molecules were prepared with the substitutions like cyano, trifluoromethyl, nitro, halo groups, methyl, and methoxy on aryl or alkyl groups. All the reaction mixtures and column eluents were monitored by TLC. Column chromatography was performed under ‘flash’ conditions. FT-IR, HRMS and NMR were recorded to find out the structure of the compounds. The anticancer activities of experimental molecules were determined using the standard MTT assay. The results demonstrated that flavone and hydantoin derivatives showed highly active against TNBC cell line. These findings may provide essential information for the development of anti-breast cancer agents.

Keywords: Triple negative breast cancer, CDK Inhibitors, Flavone, Hydantoin