人々の “健康促進” のために!

人々の “健康促進” のために!
2015年春、沖縄の琉球大学キャンパス内 (産学共同研究棟) に立ち上げた “PAK研究センター” の発足メンバー(左から4人目が、所長の多和田真吉名誉教授)
For detail, click the above image.

2008年9月23日火曜日

CEP-1347 for HD (Huntington’s Disease) Therapy

In 2002 we found that CEP-1347 is an inhibitor specific for Rac/CDC42-dependent kinases (PAKs/MLKs), and suppresses the growth of both RAS cancer and NF (neurofibromatosis) tumor cells where PAK1 is abnormally activated.

Interesting, like SAHA, CEP-1347 can pass through BBB (blood brain barrier) effectively so that it can reach brain tissues when this drug is administered systemically.

In 2003 Gillian Bates' group in London found that SAHA dramatically improves the motor impairment in HD mouse model (R6/2 mice). Like FK228, SAHA inhibits HDAC (histone deacetylase) directly, and eventually blocks the PAK1 signal pathways. However, neither FK228 nor SAHA was then available on the market. Besides, FK228 cannot cross the BBB.

In this fall Leslie Thomson’s group of UCI (University of California at Irvine) found that, like SAHA, CEP-1347 significantly reduces or delays the HD (Huntington’s Disease) symptom, both in vitro (cell culture) and in vivo (HD mouse model), suggesting that CEP-1347 and a few other anti-PAK1 drugs such as SAHA and Bio 30 could be potentially useful for the therapy of HD.

Since CEP-1347 is not available on the market as yet, it is likely that only two remedies so far available on the market, SAHA (expensive anti-CTCL drug) or Bio 30 (inexpensive healthcare product), would be used for the systemic (oral) treatment of HD patients at present. Like SAHA, Bio 30 can cross the BBB.


Mol Cell Neurosci. 2008 Sep;39: 8-20.

CEP-1347 reduces mutant huntingtin-associated neurotoxicity and restores BDNF levels in R6/2 mice.

Apostol BL, Simmons DA, Zuccato C, Illes K, Pallos J, Casale M, Conforti P, Ramos C, Roarke M, Kathuria S, Cattaneo E, Marsh JL, Thompson LM.

Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697, USA.

Huntington's disease (HD) is a devastating neurodegenerative disorder caused by an expanded polyglutamine repeat within the protein Huntingtin (Htt). We previously reported that mutant Htt expression activates the ERK1/2 and JNK pathways [Apostol, B.L.et al, 2006]. Chemical and genetic modulation of these pathways promotes cell survival and death, respectively.

Here we test the ability of two closely related compounds, CEP-11004 and CEP-1347, which inhibit Mixed Lineage Kinases (MLKs) and are neuroprotective, to suppress mutant Htt-mediated pathogenesis in multiple model systems. CEP-11004/CEP-1347 treatment significantly decreased toxicity in mutant Htt-expressing cells that evoke a strong JNK response. However, suppression of cellular dysfunction in cell lines that exhibit only mild Htt-associated toxicity and little JNK activation was associated with activation of ERK1/2. These compounds also reduced neurotoxicity in immortalized striatal neurons from mutant knock-in mice and Drosophila expressing a mutant Htt fragment.

Finally, CEP-1347 improved motor performance in R6/2 mice and restored expression of BDNF, a critical neurotrophic factor that is reduced in HD. These studies suggest a novel therapeutic approach for a currently untreatable neurodegenerative disease, HD, via CEP-1347 up-regulation of BDNF.

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