Description
EC330 is used as potential LIF inhibitors. The remaining EC330-like inhibitors include EC357, and EC363. They were designed based on the structure–activity relationship (SAR) studies on human breast cancer MCF7 cells with LIF overexpression. The SAR established through this screening includes following criteria: (i) the steroidal skeleton of the molecule is an antiprogestin, (ii) the molecule has the specific 17α-difluoro acetylenic moiety, and (iii) nonpolar substituents at position 11 are preferred over polar substituents. EC330, EC357, and EC363 have all these features. EC330 inhibits the LIF/LIF-R signaling and blocks the promoting effects of LIF on growth and migration of cancer cells.[1].
in vitro
EC330 shows marked specificity in MCF-7 cells overexpressing LIF verses MCF-7 cells. EC330 further shows cytoskeletal disruption and targeting cancer-associated fibroblasts (CAFs) through inhibition of alpha-SMA but not beta-tubulin.
in vivo
EC330 treatment (0.1, 0.5 and 2.5 mg/kg) dose dependently reduces tumor burden in ovarian (IGROV-1) and triple negative breast cancer (MDA-MB-231) cell xenografted mouse models as well as MDA-MB-231 PDX models. EC330 exhibits no reactivity towards thiol-cysteine residues, no off target binding to major receptors, kinases or ion channels. EC330 is orally bioavailable and found to be safe and tolerable in toxicity studies.
