1. Academic Validation
  2. Discovery and SAR of methylated tetrahydropyranyl derivatives as inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT)

Discovery and SAR of methylated tetrahydropyranyl derivatives as inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT)

  • J Med Chem. 2011 Jul 28;54(14):5031-47. doi: 10.1021/jm200249a.
Weston R Judd 1 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
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Myrexis, Inc., 305 Chipeta Way, Salt Lake City, Utah 84108, USA. weston.judd@myrexis.com
Abstract

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 IC(50) 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 (GI(50)) 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.

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