SMIP34 (Small Molecule Inhibitor of PELP1 34) is a first-in-class, small molecule inhibitor of estrogen receptor (ER) coregulator PELP1, binds to (Kd=37.4 uM) and reduces PELP1 oncogenic functions.
SMIP34 binds to PELP1 aa 601-866 region, and S712P mutation disrupts this interaction.
SMIP34 treatment significantly reduced the E2 induced activity of the ERE reporter in ZR75 WT- ER+ BC model cells.
SMIP34 directly interacts with PELP1, interferes with PELP1 co-activation functions, and promotes PELP1 degradation via the proteasomal pathway with EC50 of 5-10 uM in different BC model cell lines.
SMIP34 showed potent activity with an IC50 ranging from 5-10 uM in MTT assays.
SMIP34 treatment significantly reduced the E2 induced activity of the ERE reporter in ZR75 WT- ER+ BC model cells.
SMIP34 directly interacts with PELP1, interferes with PELP1 co-activation functions, and promotes PELP1 degradation via the proteasomal pathway with EC50 of 5-10 uM in different BC model cell lines in triplicate and utilized multiple WT- ER+ and TR- BC cell lines, and knock-down of PELP1 significantly reduced the activity of SMIP34.
SMIP34 significantly reduced the colony formation ability of MT- ER+ BC model cells with an IC50 of 5-10 uM, reduced the invasiveness of MT- ER+ BC models and promoted apoptosis.
SMIP34 downregulates ER signaling and enhances apoptotic pathways, SMIP34 is effective in limiting proliferation of WT- ER+ PDX tumor tissue, also reduces the proliferation of MT- ER+ CDX and PDX tumor tissue in explant assays.
SMIP34 (10-20mg/kg, daily i.p.) reduced WT- and MT- ER+ BC CDX and PDX tumor growth in vivo, significantly reduced the tumor progression and tumor weight in mice with ZR75 xenografts.