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　（Ａｌｚｈｅｉｍｅｒ‘ｓ　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.