1313603-25-6Relevant articles and documents
Discovery and SAR of methylated tetrahydropyranyl derivatives as inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT)
Judd, Weston R.,Slattum, Paul M.,Hoang, Khanh C.,Bhoite, Leena,Valppu, Liisa,Alberts, Glen,Brown, Brita,Roth, Bruce,Ostanin, Kirill,Huang, Liwen,Wettstein, Daniel,Richards, Burt,Willardsen, J. Adam
, p. 5031 - 5047 (2011/09/16)
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 μM. However, none of the cellular effects observed using ICMT inhibitors were as pronounced as those resulting from a farnesyltransferase inhibitor.
