LAUSR

Exportin 1 (XPO1/CRM1) is a key nuclear transport receptor (karyopherin) responsible for the export of different cargo proteins out of the cell’s nucleus into the cytoplasm. Its correct function is essential for cellular homeostasis, however normal XPO1 function is often disrupted in malignant cells. XPO1 is overexpressed in solid and hematological tumors and higher XPO1 expression is often associated with poorer prognosis. XPO1-regulated cargo proteins include tumor suppressor proteins and cell cycle regulators that can be involved in tumorigenesis. For example, aberrant XPO1 function may lead to cytoplasmic mislocalization of tumor suppressor proteins which results in their functional inactivation and hence may cause tumorigenesis. Inhibition of XPO1 function will restore their proper subcellular localization and function and cause tumor regression. Although XPO1 has a central role in cellular homeostasis, it is a good target for cancer therapy, as illustrated by the clinical success of the selective inhibitor of nuclear export (SINE) selinexor. Selinexor is the first and currently the only XPO1 inhibitor clinically approved. It is applied for the treatment of patients with multiple myeloma after at least one prior treatment, and for the treatment of diffuse large B cell lymphoma. Selinexor covalently binds to XPO1. The second generation SINE eltanexor is also a covalent XPO1 inhibitor but has only minimal brain penetration and consequently lower toxicity in preclinical studies. Here, we describe a novel chemical class of reversible XPO1 inhibitors with high brain penetration but with good tolerability allowing frequent dosing in preclinical models. The lead compound, FR-027, potently inhibits XPO1 function (EC50 69 ± 10 nM) and shows potent cancer cell growth inhibition in vitro of both hematological and solid cancer cell lines (EC50 50-950 nM). FR-027 is a reversible inhibitor of XPO1 and unlike many other XPO1 inhibitors it does not induce XPO1 protein degradation; this may contribute to an increased tolerability. Indeed, while it shows high brain penetration, FR-027 allows frequent dosing in mice with good tolerability (body weight). It is orally bioavailable and demonstrates strong anti-leukemic efficacy in an aggressive MOLT-4 xenograft model. Importantly, it shows potent efficacy in both an orthotopic U87 MG brain tumor xenograft model and a metastatic syngeneic ID8-fLuc ovarian cancer model with significant survival benefit as monotherapy. Altogether, these results demonstrate that FR-027 is a novel, reversible XPO1 inhibitor with important molecular and pharmacological characteristics that warrant further clinical development. Citation Format: Janne Van Hauwenhuyse, Felien Reniers, Leentje Persoons, Sam Noppen, Eline Boel, Els Vanstreels, Ann Vankerckhoven, Bert Kwanten, An Coosemans, Guy Van den Mooter, Wim Dehaen, Dirk Daelemans. A novel reversible inhibitor of XPO1 with potent efficacy in multiple preclinical mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1652.