Ac-PHSCN-NH2

Cell attachment to the extracellular matrix significantly impacts the integrity of tissues and human health. The integrin α5β1 is a heterodimer of α5 and β1 subunits and has been identified as a crucial modulator in several human carcinomas. Integrin α5β1 significantly regulates cell proliferation, angiogenesis, inflammation, tumor metastasis, and invasion. This regulatory role of integrin α5β1 in tumor metastasis makes it an appealing target for cancer therapy. The majority of the drugs targeting integrin α5β1 are limited only to clinical trials. In our study, we have performed 94287 compounds screening to determine potential drugs against α5β1 integrin. We have used ATN-161 as a reference and employed combined bioinformatic methodologies, including molecular modelling, virtual screening, MM-GBSA, cell-line cytotoxicity prediction, ADMET, Density Functional Theory (DFT), Non-covalent Interactions (NCI) and molecular simulation, to identify putative integrin α5β1 inhibitors. We found Taxifolin, PD133053, and Acebutolol that possess inhibitory activity against α5β1 integrin and could act as effective drug for the cancer treatment. Taxifolin, PD133053, and Acebutolol exhibited excellent binding to the druggable pocket of integrin α5β1, and also maintained a unique binding mechanism with extra hydrophobic contacts at molecular level. Overall, our study gives new pharmacological candidates that may act as a potential drug against integrin α5β1.

Pancreatitis is a common gastrointestinal disorder that causes hospitalization with significant morbidity and mortality. The mechanistic pathophysiology of pancreatitis is complicated, limiting the discovery of pharmacological intervention methods. Here, we show that the administration of ATN-161, an antagonist of Integrin-α5, significantly mitigates the pathological condition of acute pancreatitis induced by caerulein. We find that CK19-positive pancreatic ductal cells align parallel to blood vessels in the pancreas. In the caerulein-induced acute pancreatitis model, the newly emergent CK19-positive cells are highly vascularized, with a significant increase in vascular density and endothelial cell number. Single-cell RNA sequencing analysis shows that ductal and endothelial cells are intimate interacting partners, suggesting the existence of a ductal-endothelial interface in the pancreas. Pancreatitis dramatically reduces the crosstalk in the ductal-endothelial interface but promotes the Spp-1/Integrin-α5 signaling. Blocking this signaling with ATN-161 significantly reduces acinar-to-ductal metaplasia, pathological angiogenesis, and restores other abnormal defects induced by caerulein. Our work reveals the therapeutic potential of ATN-161 as an uncharacterized pharmacological method to alleviate the symptoms of pancreatitis.