| Autor: |
Judd WR; Department of Medicinal Chemistry, Myrexis, Inc., 305 Chipeta Way, Salt Lake City, Utah 84108, USA. weston.judd@myrexis.com, Slattum PM, Hoang KC, Bhoite L, Valppu L, Alberts G, Brown B, Roth B, Ostanin K, Huang L, Wettstein D, Richards B, Willardsen JA |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2011 Jul 28; Vol. 54 (14), pp. 5031-47. Date of Electronic Publication: 2011 Jun 28. |
| DOI: |
10.1021/jm200249a |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
