5HA9

Crystal structure-based design and disovery of a novel PARP1 antiagonist (BL-PA10) that induces apoptosis and inhibits metastasis in triple negative breast cancer

Summary for 5HA9

• Entry DOI: 10.2210/pdb5ha9/pdb
• Descriptor: Poly [ADP-ribose] polymerase 1, GLYCEROL, SULFATE ION, ... (4 entities in total)
• Functional Keywords: inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 79694.08

Authors

Fu, L.,Peng, H.,Zhang, L.,Ouyang, L. (deposition date: 2015-12-30, release date: 2016-03-09, Last modification date: 2024-03-20)

Primary citation

Fu, L.,Wang, S.,Wang, X.,Wang, P.,Zheng, Y.,Yao, D.,Guo, M.,Zhang, L.,Ouyang, L.
Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer.
Sci Rep, 6:3-3, 2016

PubMed Abstract: Poly (ADP-ribose) polymerase-1 (PARP1) is a highly conserved enzyme focused on the self-repair of cellular DNA damage. Until now, numbers of PARP inhibitors have been reported and used for breast cancer therapy in recent years, especially in TNBC. However, developing a new type PARP inhibitor with distinctive skeleton is alternatively promising strategy for TNBC therapy. In this study, based on co-crystallization studies and pharmacophore-docking-based virtual screening, we discovered a series of dihydrodibenzo[b,e]-oxepin compounds as PARP1 inhibitors. Lead optimization result in the identification of compound OL-1 (2-(11-(3-(dimethylamino)propylidene)-6,11- dihydrodibenzo[b,e]oxepin )-2-yl)acetohydrazide), which has a novel chemical scaffold and unique binding interaction with PARP1 protein. OL-1 demonstrated excellent potency (inhibiting PARP1 enzyme activity with IC = 0.079 μM), as well as inhibiting PARP-modulated PARylation and cell proliferation in MDA-MB-436 cells (BRAC1 mutation). In addition, OL-1 also inhibited cell migration that closely related to cancer metastasis and displayed remarkable anti-tumor efficacy in MDA-MB-436 xenograft model without apparent toxicities. These findings highlight a new small-molecule PAPR1 inhibitor (OL-1) that has the potential to impact future TNBC therapy.

PubMed: 28442756
DOI: 10.1038/s41598-016-0007-2

Experimental method

X-RAY DIFFRACTION (4.01 Å)