Abstract PR1: In silico designed covalent peptidomimetic inhibitors (KPT-SINE) of CRM1 modulate tumor suppressor protein nuclear export and induce apoptosis in cancer cells

Chromosome region maintenance 1/Exportin-1 (CRM1) is a key nuclear export protein whose inhibition leads to nuclear accumulation of tumor suppressor (TSP) and growth regulatory proteins (GRP). Through CRM1 inhibition, nuclear localization of these proteins restores cell cycle checkpoints and genome surveying functions culminating in apoptosis of tumor cells. Conversely, CRM1 inhibition of normal cells induces reversible cell cycle arrest. We developed a structural model of CRM1 suited for binding diverse small molecules and used it to guide the discovery and development of KPT-SINE (selective inhibitors of nuclear export). The model predicted that a switching motion of Met545 and Met583 in CRM1 was required for inhibitor accommodation. We found that published CRM1 inhibitors display efficient mimicry of cargo Nuclear Export Signals (NES) and a thiol reactive warhead proximal to Cys528 in CRM1. This was further confirmed by Yuh Min Chook who solved the X-ray structures of CRM1. In silico screening yielded 402 hits (from a library of ˜250,000 drug-like compounds) with 19 molecules active in vitro (IC50