Abstract
Novel PARP inhibitors with selective mode-of-action have been approved for clinical use. Herein, oxadiazole based ligands that are predicted to target PARP-1 have been synthesized and screened for the loss of cell viability in mammary carcinoma cells, wherein seven compounds were observed to possess significant IC50 values in the range of 1.4 to 25 µM. Furthermore, compound 5u, inhibited the viability of MCF-7 cells with an IC50 value of 1.4µM, when compared to Olaparib (IC50 = 3.2 µM). Compound 5s also decreased cell viability in MCF-7 and MDA-MB-231 cells with IC50 values of 15.3 and 19.2 µM, respectively. Treatment of MCF-7 cells with compounds 5u and 5s produced PARP cleavage, H2AX phosphorylation and CASPASE-3 activation comparable to that observed with Olaparib. Compounds 5u and 5s also decreased foci-formation and 3D Matrigel growth of MCF-7 cells equivalent to or greater than that observed with Olaparib. Finally, in silico analysis demonstrated binding of compound 5s towardsthe catalytic site of PARP-1, indicating that these novel oxadiazoles synthesized herein may serve as exemplars for the development of new therapeutics in cancer.
Highlights
Loss of function mutation of breast cancer genes 1/2 (BRCA1 and BRCA2) significantly increases the risk of development and progression of breast and other cancers [1]
Preclinical investigations determined that dysfunction of BRCA1/2 results in sensitization of cancer cells to the catalytic inhibition of Poly ADP-ribose polymerase (PARP), producing cell-cycle arrest followed by apoptosis [2]
This vulnerability initially allowed pharmacological inhibition of PARP to be exploited in BRCA1/2 deficient cancer, which is being extended to BRCA proficient cancer [3,4,5]
Summary
Loss of function mutation of breast cancer genes 1/2 (BRCA1 and BRCA2) significantly increases the risk of development and progression of breast and other cancers [1]. Preclinical investigations determined that dysfunction of BRCA1/2 results in sensitization of cancer cells to the catalytic inhibition of Poly ADP-ribose polymerase (PARP), producing cell-cycle arrest followed by apoptosis [2]. Such as chromatin structure, gene transcription, DNA repair, and apoptosis [7] Substrate mimetic compounds such as nicotinamide and 3-aminobenzamide were reported as weak PARP1 inhibitors with poor specificity, prompting chemists to design potent and specific PARP-1 inhibitors for clinical use [8,9,10]. A number of PARP inhibitors (PARPis) with differing PARP trapping capacity have been clinically approved or received FDA Orphan Drug designation (Veliparib), including Olaparib, Talazoparib, and Rucaparib (Figure 1) [11] Both pre-clinical studies and clinical data demonstrate either intrinsic resistance to PARP inhibition or the development of acquired resistance to PARPi, resulting in limitation of the clinical response to the currently approved PARPis [12,13,14,15]. Molecules 2022, 27, 703 compounds in BRCA wild-type estrogen receptor positive (ER+) and triple-negative breast cancer (TNBC) cells is reported
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