Editors' ChoiceDrug Discovery

SINES of a New Leukemia Treatment

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Science Translational Medicine  24 Oct 2012:
Vol. 4, Issue 157, pp. 157ec193
DOI: 10.1126/scitranslmed.3005160

Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia that is currently incurable. CLL manifests because B lymphocytes fail to die as a result of aberrant activation of survival signals. Dysfunctional tumor suppressor proteins (TSPs) are either silenced or sequestered in the cytoplasm and cannot detect DNA damage and promote cell death. XPO1, a major nuclear export protein that transports TSPs into the cytoplasm, is overexpressed or mutated in a variety of cancers, including CLL. Now, using in silico docking methods that specifically target XPO1, Lapalombella et al. developed selective inhibitors of nuclear export (SINEs).

XPO1 has been shown to be a viable cancer target in solid tumors, but previous attempts at developing an XPO1-targeting drug have been unsuccessful because of nonspecific off-target effects. Using in vitro studies, the authors showed that the SINEs—KPT-185 and KPT-251—specifically inhibited the formation of XPO1-cargo complexes with no detectable binding to other proteins; caused accumulation of TSPs such as Akt, FoxO3a, IκB, and p53 in the nucleus; and induced apoptosis of primary CLL cells, especially a genetically unfavorable subset. KPT-185 was also effective in the presence of a protective CLL microenvironment and had minimal effects on normal immune cells. In vivo studies in a mouse model of CLL showed that treatment with KPT-251, which demonstrated better pharmacokinetics and oral bioavailability as compared with those of KPT-1855, led to a significant improvement in survival when compared with control mice.

These data provide support for further research into the development of SINEs as orally bioavailable, selective, and irreversible therapeutic agents that target a key step in the pathogenesis of CLL and perhaps other related lymphoproliferative disorders.

R. Lapalombella et al., Selective inhibitors of nuclear export (SINE) show that CRM1/XPO1 is a target in chronic lymphocytic leukemia. Blood, 3 October 2012 (10.1182/blood-2012-05-429506). [Abstract]

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