2016年5月23日月曜日

Converting the TOR inhibitor AZD2014 to a potent PAK1-specific inhibitor

A few years ago, a group of AstraZeneca (led by Dr. Kurt Pike) in UK developed a series of TOR inhibitors for cancer therapy (1).  


http://www.soci.org/news/fine-chems/kinase-kurt-pike-speaker-interview

One of them called AZD2014 is an ATP antagonist having an N-methyl amide group. If this amide bond is cleaved,  and N-methyl group is replaced by a water-soluble bulky alcohol through  the Click Chemisry, AZD2014 could be converted to a      potent highly cell-permeable PAK1 inhibitor useful for therapy of cancers and many other PAK1-dependent diseases/disorders such as AD (Alzheimers disease). 

Unlike many other kinases, PAK1 has an extra large ATP-binding pocket, that could accomodate  a series of bulky ATP antagonists. Thus、the bulky AZD 2014 ester called PRC-16AZ could serve as a potent ”highly PAK1-specific” inhibitor. 

References:

1. Pike KG, Malagu K, Hummersone MG, Menear KA, Duggan HM, Gomez S, Martin NM, Ruston L, Pass SL, Pass M. Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014. Bioorg Med Chem Lett. 2013 ; 23: 1212-6.

 

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