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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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Judd WR,Slattum PM,Hoang KC,Bhoite L,Valppu L,Alberts G,Brown B,Roth B,Ostanin K,Huang L,Wettstein D,Richards B,Willardsen JA

doi

10.1021/jm200249a

subject

Has Abstract

pub_date

2011-07-28 00:00:00

pages

5031-47

issue

14

eissn

0022-2623

issn

1520-4804

journal_volume

54

pub_type

杂志文章

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