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Karyopharm Therapeutics announces the Publication of Two Preclinical Studies on the Activity of Selective Inhibitors of Nuclear Export (SINE) in Acute Myeloblastic Leukemia (AML)
Date:8/1/2012

NATICK, Mass., Aug. 1, 2012 /PRNewswire/ -- Karyopharm Therapeutics Inc., a leader in the new field of nuclear transport modulators, announced publication of preclinical models utilizing their proprietary SINE compounds in AML. SINEs specifically and irreversibly inhibit the nuclear transporter exportin 1 (XPO1), more commonly called CRM1 (chromosome region maintenance 1). CRM1 is the exclusive mediator of the nuclear export of p53, p73, pRb, FOXO, p21, p27, BRACA1, and other tumor suppressor proteins, along with the endogenous inhibitor of Nuclear Factor kB (NF-kB) known as IkB. Cancer cells use nuclear export of these key anti-tumor proteins to functionally inactivate them. Blockade of CRM1 with SINE leads to accumulation and activation of tumor suppressor and chemotherapy resistance proteins in the nucleus, leading to selective tumor cell apoptosis while sparing normal cells.

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Romero Garzon, MD, PhD, and colleagues at the Ohio State University published a plenary paper in the journal Blood entitled, "Pre-clinical activity of a novel CRM1 inhibitor in acute myeloid leukemia" (PubMed ID: 22677130). The authors showed that Karyopharm's SINE compounds induced apoptosis at nanomolar levels in AML cell lines and in AML blasts from patients. SINEs reduced the levels of the AML oncoprotein FLT3, and when given orally to mice, prolonged their survival with good tolerability.

In the second paper, Tom Look, MD, and colleagues at the Dana Farber Cancer Institute in Boston published a paper in the journal Leukemia entitled "Anti-leukemic activity of nuclear export inhibitors that spare normal hematopoietic cells" (PubMed ID: 22847027). This paper describes the discovery of the SINE compounds based on the X-ray crystal structure of CRM1 using proprietary in silico screening methods developed by Karyopharm's fo
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SOURCE Karyopharm Therapeutics Inc.
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