Revolutionizing Cancer Therapy: The Potential of SL-801 as a Reversible XPO1 Inhibitor with Potent Anti-Cancer Efficacy

The main nuclear export protein in eukaryotic cells, XPO1/CRM1, is crucial for the transport of proteins and RNAs between the nucleus and the cytoplasm. Its overexpression is linked to various cancers, leading to abnormal protein distribution, uncontrolled cell growth, and resistance to cell death, which are associated with severe cancer traits and worse patient outcomes. XPO1 has been identified as a significant target for cancer therapy, with nuclear export inhibitors showing potential as a new class of anti-cancer drugs effective against a range of cancers.

SL-801 is a newly discovered small molecule that forms a covalent bond with Cys528 in XPO1, preventing its interaction with substrates like p53, FOXO, p21, p27, and others. Unlike leptomycin B, which irreversibly binds to XPO1 and has shown significant toxicity in clinical trials, SL-801's binding to XPO1 is reversible, which could be advantageous for optimizing its therapeutic effectiveness. SL-801 has been shown to strongly inhibit XPO1-mediated nuclear export, leading to cell cycle arrest and the induction of apoptosis in a time- and dose-dependent manner.

The anti-tumor efficacy of SL-801 was tested against a wide variety of 240 cell lines, encompassing both solid and hematologic cancers, and confirmed in several SCID mouse xenograft models. The OncoPanel high content screening platform was utilized to assess SL-801's cytotoxicity against 205 solid tumor and 35 liquid tumor cell lines. SL-801 exhibited potent activity, with many cell lines showing growth inhibition at concentrations ≤ 10 nM and nearly all at concentrations ≤ 100 nM. Sensitivity to SL-801 was not dependent on the rate of cell proliferation or XPO1 expression levels, although hematopoietic cell lines showed greater sensitivity.

Furthermore, SL-801 induced apoptosis in nearly half of the cell lines tested, as evidenced by an increase in active caspase-3 staining. Analysis of the cell line cytotoxicity screen against genomic datasets revealed that SL-801's cytotoxicity was not influenced by the mutation status of key oncogenes or tumor suppressor genes.

The in vitro findings were corroborated in several xenograft models in SCID mice, showing significant tumor growth inhibition and prolonged survival with well-tolerated doses. Notably, in multiple myeloma and non-small cell lung cancer models, SL-801 demonstrated substantial anti-tumor activity.

These results indicate that SL-801 is a promising drug candidate that targets a clinically validated pathway and has potential for development in various oncological indications. Its reversible binding to XPO1 may allow for dosing schedules that promote recovery in normal tissues, thus expanding the therapeutic window. Preclinical work is in progress to facilitate clinical trial entry, and the design for a Phase I trial will be discussed.