ERK inhibitor(Kura Oncology)

Perfluorooctane sulfonate (PFOS), a pervasive environmental contaminant, is ubiquitously detected in water, air, soil, and food chains. Emerging evidence has implicated PFOS in the pathogenesis of cardiovascular diseases, particularly atherosclerosis - the fundamental pathological process underlying diverse cardiovascular and cerebrovascular disorders. A previous study demonstrated that PFOS exacerbates atherosclerosis in apolipoprotein E-deficient (ApoE^-/-) mice through pro-inflammatory M1 macrophage polarization. However, the effects of PFOS on vascular smooth muscle cells (VSMCs) and their contribution to intimal hyperplasia and atherosclerosis remain unexplored. Our in vitro investigations revealed that PFOS potentiates proliferation, migration, and phenotypic switching in primary human aortic smooth muscle cells (HASMCs). Moreover, we also demonstrated that PFOS exposure aggravated neointimal formation in a femoral artery injury model and promoted atherosclerosis. To elucidate the role of VSMCs in these processes in vivo, we established a VSMCs lineage-tracing model utilizing Myh11-Cre/ERT2; R26-tdTomato; ApoE^-/- mice. Following 16 weeks of PFOS exposure, atherosclerotic plaque progression exhibited a positive correlation with intraplaque VSMCs accumulation. RNA sequencing analysis and subsequent validation confirmed PFOS-induced tissue plasminogen activator (tPA) upregulation in VSMCs at both transcriptional and translational levels. Notably, tPA knockdown abrogated PFOS-driven proliferation, migration, and phenotypic switching in HASMCs. Mechanistic studies revealed ERK signaling pathway activation as the primary mediator of PFOS-induced tPA expression. Collectively, these findings provide novel mechanistic insights into how PFOS aggravates intimal hyperplasia and atherosclerosis, highlighting its role in exacerbating cardiovascular pathogenesis. They further suggest that ERK inhibitors may mitigate the detrimental effects of PFOS on the vasculature.

The mitogen-activated protein kinase (MAPK) pathway-also known as the RAS/RAF/MEK/ERK pathway-is a critical signalling cascade involved in regulating cell growth, proliferation, and survival. First discovered in the early 1980s, the pathway's extracellular signal-regulated kinase (ERK) subfamily was identified in the 1990s. The ERK family includes several isoforms-ERK1, ERK2, ERK3, ERK5, and ERK6-with ERK1 (MAPK3) and ERK2 (MAPK1) being the most well-characterised and playing central roles in MAPK signalling. Deregulation of ERK signalling (commonly referred to as the ERK pathway or ERKp) has been implicated in approximately 40% of human cancers. This review focuses on the structural insights of ERK1/2 and their critical role in the MAPK signalling cascade. Despite their clinical significance, no ERK inhibitors have yet been approved by the FDA. Several molecules-such as SCH772984, SCH900353, ulixertinib (BVD-523), CC-9003, KO-947, AZD0364, norathyriol, and FR180204-are currently in preclinical or clinical trial stages. This review also highlights recent advances in the design and synthesis of ERK inhibitors, emphasising their structural uniqueness and potential to inhibit mutant forms of ERK1/2. Finally, we discuss future directions for the development of ERK1/2 inhibitors as FDA-approved cancer therapeutics.