Discovery and SAR of Methylated Tetrahydropyranyl Derivatives as Inhibitors of Isoprenylcysteine Carboxyl Methyltransferase (ICMT)

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• 作者：Weston R. Judd ; Paul M. Slattum ; Khanh C. Hoang ; Leena Bhoite ; Liisa Valppu ; Glen Alberts ; Brita Brown ; Bruce Roth ; Kirill Ostanin ; Liwen Huang ; Daniel Wettstein ; Burt Richards ; J. Adam Willardsen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：July 28, 2011
• 年：2011
• 卷：54
• 期：14
• 页码：5031-5047
• 全文大小：1179K
• 年卷期：v.54,no.14(July 28, 2011)
• ISSN：1520-4804

文摘

A series of tetrahydropyranyl (THP) derivatives has been developed as potent inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT) for use as anticancer agents. Structural modification of the submicromolar hit compound 3 led to the potent 3-methoxy substituted analogue 27. Further SAR development around the THP ring resulted in an additional 10-fold increase in potency, exemplified by analogue 75 with an IC₅₀ of 1.3 nM. Active and potent compounds demonstrated a dose-dependent increase in Ras cytosolic protein. Potent ICMT inhibitors also reduced cell viability in several cancer cell lines with growth inhibition (GI₅₀) values ranging from 0.3 to >100 渭M. However, none of the cellular effects observed using ICMT inhibitors were as pronounced as those resulting from a farnesyltransferase inhibitor.