Snail IN-1

Snail IN-1 is an orally active inhibitor of Snail with a target Ka of 0.36 μM. It disrupts the Snail-CBP interaction, promoting Snail protein degradation by reducing acetylation and increasing polyubiquitination levels, without affecting other EMT transcription factors. Snail IN-1 alleviates atherosclerotic plaque burden, regulates inflammation and plaque stability-related factors, downregulates CCL5, CXCL10, MMP2, and MMP9, while upregulating α-smooth muscle actin. It exhibits anti-inflammatory and plaque stabilizing activities, making it useful for atherosclerosis research.

Snail IN-1 (compound S29) effectively downregulates Snail protein levels in HUVECs in a concentration-dependent manner without altering Snail mRNA levels, indicating its post-transcriptional regulatory action. At concentrations up to 60 μM for 48 hours, Snail IN-1 shows no significant cytotoxicity to HUVECs. It accelerates Snail protein degradation, decreasing its stability at 5 μM for 0-240 minutes. Snail IN-1 (2.5-20 μM; 48 h) specifically reduces Snail protein levels in HUVECs without affecting other EMT transcription factors (Zeb1, Slug, Twist). At 5 μM for 24 hours, Snail IN-1 promotes Snail degradation by disrupting Snail's interaction with CBP, reducing its acetylation, and increasing its polyubiquitination in HUVECs. Furthermore, Snail IN-1 (2.5 μM; 24 h) significantly downregulates mRNA levels of pro-atherosclerotic factors (CCL5, CXCL10, MMP-9, MMP-2) in TNF-α stimulated HUVECs and inhibits protein expression of CCL5 and CXCL10 in a concentration-dependent manner at 1.25-5 μM for 24 hours. It can impair monocyte recruitment by altering the secretion profile of TNF-α stimulated HUVECs at 2.5 μM for 24 hours.

Snail IN-1, administered orally at 25-50 mg/kg daily for 4 weeks, exhibits a dose-dependent anti-atherosclerotic effect in high-fat diet-fed ApoE -/- mice by reducing plaque burden through the decrease of inflammatory chemokines (CCL5, CXCL10) and matrix degradation enzymes (MMP2, MMP9), while enhancing plaque stability factors (collagen, α-SMA). At a single dose of 2000 mg/kg, Snail IN-1 demonstrates good tolerance in C57BL/6 mice, causing no acute organ damage or functional impairment.