title: Discovery and SAR of methylated tetrahydropyranyl derivatives as inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT).
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.
authors.affiliation: Department of Medicinal Chemistry, Myrexis, Inc., 305 Chipeta Way, Salt Lake City, Utah 84108, USA. weston.judd@myrexis.com
authors.forename: Weston R
authors.initials: WR
authors.lastname: Judd
authors.forename: Paul M
authors.initials: PM
authors.lastname: Slattum
authors.forename: Khanh C
authors.initials: KC
authors.lastname: Hoang
authors.forename: Leena
authors.initials: L
authors.lastname: Bhoite
authors.forename: Liisa
authors.initials: L
authors.lastname: Valppu
authors.forename: Glen
authors.initials: G
authors.lastname: Alberts
authors.forename: Brita
authors.initials: B
authors.lastname: Brown
authors.forename: Bruce
authors.initials: B
authors.lastname: Roth
authors.forename: Kirill
authors.initials: K
authors.lastname: Ostanin
authors.forename: Liwen
authors.initials: L
authors.lastname: Huang
authors.forename: Daniel
authors.initials: D
authors.lastname: Wettstein
authors.forename: Burt
authors.initials: B
authors.lastname: Richards
authors.forename: J Adam
authors.initials: JA
authors.lastname: Willardsen
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D055786:Gene Knockout Techniques; D006801:Humans; D011496:Protein Methyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D018631:ras Proteins / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D011714:Pyrans; D011994:Recombinant Proteins; D011496:Protein Methyltransferases; C056501:protein-S-isoprenylcysteine O-methyltransferase; D018631:ras Proteins