SMIP004

SMIP004 is an inhibitor of the E3 ubiquitin ligase S-phase kinase-associated protein 2 (SKP2).¹ It reduces the levels of SKP2 and induces the accumulation of p27^Kip1 and p21^Cip21, ubiquitination targets of SKP2, in LNCaP-S14 human prostate cancer cells overexpressing SKP2 when used at a concentration of 40 µM. SMIP004 is cytotoxic to LNCaP-S14 cells (IC₅₀ = 1.09 µM) but not non-cancerous IMR-90 human fibroblasts. It also targets cyclin D1 for proteasomal degradation, as well as induces the unfolded protein response, oxidative stress, apoptosis, and cell cycle arrest at the G₁ phase in LNCaP-S14 cells.² SMIP004 (2 mg/kg) reduces immobility time in the forced swim test and tail suspension test, as well as increases the preference for sucrose in the sucrose preference test, in a mouse model of chronic unpredictable stress-induced depression.

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1. Rico-Bautista, E., Yang, C.C., Lu, L., et al. Chemical genetics approach to restoring p27Kip1 reveals novel compounds with antiproliferative activity in prostate cancer cells. BMC Biol. 8, 153 (2010).

2. Rico-Bautista, E., Zhu, W., Kitada, S., et al. Small molecule-induced mitochondrial disruption directs prostate cancer inhibition via UPR signaling. Oncotarget. 4(8), 1212-1229 (2013).