The past, present, and future of CRM1/XPO1 inhibitors

Abstract

Therapies targeted at inhibiting nucleo-cytoplasmic transport have found broad applications in the field of oncology. Chromosome region maintenance 1 (CRM1), better known as exportin 1 (XPO1), is the protein transporter responsible for the nucleo-cytoplasmic shuttling of most of the tumor suppressor proteins (TSP) and growth regulatory factors. XPO1 is also upregulated in many malignancies and associated with a poor prognosis. Its inhibition has been a target of therapy, and hence, the selective inhibitors of nuclear transport (SINE) compounds were developed as a novel class of anti-cancer agents. The most well-known SINE agent is selinexor (KPT-330) and has been widely tested in phase I and II clinical trials in both solid tumors and hematologic malignancies. This review discusses how dysregulation of XPO1 promotes tumorigenesis, the historical considerations in the development of SINE compounds, and their role in current clinical therapies.

Peptide:MHC dependent activation of natural killer cells through KIR2DS2 generates anti-tumor responses

“…This peptide was derived from the XPO1 (exportin-1/CRM1) protein, which is thought to function as the sole nuclear exporter for many different tumor suppressor and growth regulatory proteins including p53, p27, FOXO1, IkB, cyclin B1, cyclin D1 and survivin (38). XPO1 is overexpressed and associated with poor prognosis in multiple cancers including hematological malignancies and difficult to treat cancers such as pancreatic cancer and HCC (41,43,47). Inhibition of XPO1 is gaining traction as a cancer therapeutic target following clinical trials, and our data suggest it could also be a target for KIR2DS2based NK cell therapeutics (40).…”

Xpo7 negatively regulates Hedgehog signaling by exporting Gli2 from the nucleus

“…Taking all these findings together, we postulate that Xpo7 is a regulator of the Hh pathway that cooperates with SuFu in excluding Gli2/3 from the nucleus and facilitating the maintenance of the "OFF" state for Hh signaling in the absence of ligand. Given that drugs targeting nuclear export pathways have recently found their way to the clinic (40), our data may be the stepping stone towards designing novel therapeutics against Gli-dependent tumors. (16).…”

Caffeic acid phenethyl ester (CAPE): pharmacodynamics and potential for therapeutic application

“…CAPE targets specifically a non-catalytic cysteine 528 of XPO1/ CRM1, which results in inhibition of its function. (Wang and Liu 2019). Among the target proteins of XPO1/CRM1 are NF-κB, Wnt/β-catenin, PI3K/Akt, p53, FOXOs (Forkhead box proteins), etc.…”

“…Among the target proteins of XPO1/CRM1 are NF-κB, Wnt/β-catenin, PI3K/Akt, p53, FOXOs (Forkhead box proteins), etc. (Wang and Liu 2019). It has been reported that XPO1/CRM1 inhibitors are among the anticancer agents with the broadest spectrum of activity towards diverse malignancies (Wang and Liu 2019).…”

“…(Wang and Liu 2019). It has been reported that XPO1/CRM1 inhibitors are among the anticancer agents with the broadest spectrum of activity towards diverse malignancies (Wang and Liu 2019). They exert anti-inflammatory effects in preclinical models of neurodegeneration (Haines et al 2015), which could be also the mechanism of the antineoplastic and anti-inflammatory effects of CAPE.…”