Design and Synthesis of Novel Poly ADP Ribose Polymerase 1 (PARP1) Inhibitors for Treatment of Solid Tumors

Abstract

Poly ADP-Ribose Polymerase 1 (PARP1) is one of the potential target for treatment of cancer, specifically for breast and ovarian cancer. There are currently three FDA approved PARP1 inhibitors namely Olaparib, Rucaparib and Niraparib in market while Talazoparib are in late stage of clinical development. All these molecules are non-selective PARP1 inhibitors with concurrent inhibition of PARP2 with similar potency, which may cause toxicities like acute myeloid leukemia, myelodysplastic syndrome and GI toxicity. Overall, looking at the success rate of PARP1 inhibitors into various solid tumors, there is an urge of novel and selective PARP1 inhibitors. With the aim of designing next generation PARP1 inhibitors, a ligand based drug design approach; 3D-QSAR study was performed on a series of 2,3-Dihydrobenzofuran-7-carboxamide derivatives reported as PARP1 inhibitors. Total dataset of 31 molecules divided into training set (23) and test set (8) in 75:25 ratio. Three different alignment methods were used and amongst them distill based alignment was found to be significant. Contour map analysis of best COMFA and COMSIA model suggested donor, acceptor, steric and hydrophobic favourable groups as important ligand features. Eleven diversified molecules with similar PARP1 assay method used to develop a pharmacophore model using DISCOTECH module, which was refined by GASP in SYBYL.X software. The best model generated three types of pharmacophoric features namely, hydrogen bond donor (HBD), hydrogen bond acceptor (HBA) and one hydrophobic (HYD). The predictive power of pharmacophore model was then validated using GH score and ROC curve method. The results obtained from total of 551 dataset (51 Actives + 500 Decoy) as GH score is 0.952 and Enrichment factor (E) is 9.58. Finally, this model was screened against NCI library and total 6992 hits were obtained after applying various filters. Highest Qfit compounds then subjected to molecular docking in the active site of PARP1 (PDB ID: 4PJT, BMN-673) and PARP2 (PDB ID: 4TVJ, Olaparib) using GOLD software. Highest Gold score compounds were chosen which led to the discovery of new virtual hit compounds as potential PARP1 inhibitors. Amongst 30 designed molecules, nine derivatives consisting of novel benzoxazin-4-one ring synthesized. To assess the potency of synthezied compounds, Invitro activity on BRCAm cancer cell line (MDA-MB-436) was performed using MTT assay and compound PJ-BD-02 and PJ-BD-04 was found to be potent with 50.383% and 51.241% inhibition at 100µM concentration.