Ilomastat

Aberrant BMPR2 (bone morphogenetic protein receptor 2) signaling is associated with the pathogenesis of pulmonary hypertension. SMAD4 (mothers against decapentaplegic homolog 4) is an essential downstream effector of BMPR2 signaling, but whether and how it participates in pulmonary hypertension are unclear.

Globally and vascular cell-specifically inducible knockout mouse models were used to examine the role of SMAD4 deficiency in differential cell compartments in the development of pulmonary hypertension. Single-cell transcriptomic analysis in combination with in vitro cell function measurements was conducted to provide mechanistic insights into pulmonary hypertension pathogenesis.

Adult mice with Smad4 global deletion or endothelial cell-specific deletion spontaneously developed pulmonary hypertension manifestations, characterized by elevated right ventricle systolic pressure and excessive muscularization in pulmonary distal vessels, which were accompanied by other cardiovascular abnormalities. By contrast, mice with smooth muscle cell-specific Smad4 deletion had no pulmonary hypertension but rather displayed evident aortic aneurysm and dissection. At the cellular level, SMAD4 deficiency led to impairment of both endothelial cell-cell and cell-matrix adhesions and disorganized ECM (extracellular matrix), resulting in increased vascular leak and weakened endothelium-matrix attachment. Notably, endothelial Itgb1 deletion mimicked the impact of endothelial Smad4 loss on pulmonary hypertension. Finally, enhancing endothelial cell adhesion and ECM assembly by administrating an MMP (matrix metallopeptidase) inhibitor ilomastat could alleviate the pulmonary hypertension manifestations caused by endothelial SMAD4 deficiency.

SMAD4 deficiency in endothelial cells, but not smooth muscle cells, plays a pathogenic role in pulmonary hypertension, via dampening endothelial cell-cell and cell-matrix adhesions and ECM organization.

The T790M secondary mutation in EGFR confers therapeutic resistance to EGFR-TKIs, leading to poor outcomes. Non-small-cell lung cancer (NSCLC) harboring EGFR T790M mutation is incurable and there is an urgent need for improved therapeutics. Here we report the identification of a small compound, MG-3C, that kills NSCLC cells with T790M mutation while sparing lung cancer cells without T790M mutation. We found that MG-3C activity targets EGFR-STAT3 signaling pathway in NSCLC through direct inhibition of matrix metalloproteinase 9 (MMP-9), ultimately leading to G2/M phase arrest, growth inhibition and apoptosis. Compared with the reported MMP-9 inhibitor Ilomastat, MG-3C shows high anticancer activity and affinity for targets. MG-3C forms hydrogen bonds with the ASP-113, ASP-201 and HIS-203 amino acid residues of MMP-9 with a docking fraction of -9.04 kcal/mol, while Ilomastat forms hydrogen bonds with the GLN-169, ASP-201 and HIS-203 amino acid residues of MMP-9 with a docking fraction of -5.98 kcal/mol. The spatial structure composed of ASP-113, ASP-201, and HIS-203 of MMP-9 provides a new coordinate for the design of MMP-9 inhibitors. Most importantly, subcutaneous and oral administration of MG-3C elicit dramatic regression of NSCLC xenograft tumors harboring T790M mutation as well as favorable biosafety profile in vivo, suggesting that MG-3C may be a potential candidate for NSCLC harboring T790M mutation.