Cancer cells are able inactivate the function of tumour suppressor proteins (TSPs) by overexpressing the nuclear export protein, XPO1, which results in TSP mislocalisation to the cytopasm. Pharmacological inhibition of XPO1 in cancer cells promotes nuclear retention of TSP cargo proteins such as p53, Foxo, and BRCA1, and this activity restores TSP function and leads to cycle arrest and enhanced cancer cell apoptosis. This approach is being expoited as a novel anti-cancer mechanism [4,6].

1. Chen YF, Shen Y, Yan DF, Ghazala M, Scemama de Gialluly MA, Srinivasan R, Farrar AN, Friedrich RM, Adams DJ. (2024) Electrophile Determines Cellular Phenotypes among XPO1-Targeting Small Molecules. J Med Chem, 67 (14): 12033-12054. [PMID:39005064]

2. Etchin J, Berezovskaya A, Conway AS, Galinsky IA, Stone RM, Baloglu E, Senapedis W, Landesman Y, Kauffman M, Shacham S et al.. (2017) KPT-8602, a second-generation inhibitor of XPO1-mediated nuclear export, is well tolerated and highly active against AML blasts and leukemia-initiating cells. Leukemia, 31 (1): 143-150. [PMID:27211268]

3. Hing ZA, Fung HY, Ranganathan P, Mitchell S, El-Gamal D, Woyach JA, Williams K, Goettl VM, Smith J, Yu X et al.. (2016) Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies. Leukemia, 30 (12): 2364-2372. [PMID:27323910]

4. Mendonca J, Sharma A, Kim HS, Hammers H, Meeker A, De Marzo A, Carducci M, Kauffman M, Shacham S, Kachhap S. (2014) Selective inhibitors of nuclear export (SINE) as novel therapeutics for prostate cancer. Oncotarget, 5 (15): 6102-12. [PMID:25026284]

5. Sandanayaka VP, Shacham S, Kauffman M, Schechter S, Mccauley D, Landesman Y, Senapedis W, Saint-Martin J-R. (2013) Nuclear transport modulators and uses thereof. Patent number: WO2013019561A1. Assignee: Karyopharm Therapeutics, Inc.. Priority date: 29/07/2011. Publication date: 04/07/2013.

6. Senapedis WT, Baloglu E, Landesman Y. (2014) Clinical translation of nuclear export inhibitors in cancer. Semin Cancer Biol, 27: 74-86. [PMID:24755012]

7. Vercruysse T, De Bie J, Neggers JE, Jacquemyn M, Vanstreels E, Schmid-Burgk JL, Hornung V, Baloglu E, Landesman Y, Senapedis W et al.. (2017) The Second-Generation Exportin-1 Inhibitor KPT-8602 Demonstrates Potent Activity against Acute Lymphoblastic Leukemia. Clin Cancer Res, 23 (10): 2528-2541. [PMID:27780859]