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Functionalized indoleamines as potent, drug-like inhibitors of isoprenylcysteine carboxyl methyltransferase (Icmt).

Publication ,  Journal Article
Ramanujulu, PM; Yang, T; Yap, S-Q; Wong, F-C; Casey, PJ; Wang, M; Go, M-L
Published in: Eur J Med Chem
May 2013

The enzyme isoprenylcysteine carboxyl methyltransferase (Icmt) plays an important role in the post-translational modification of proteins involved in the regulation of cell growth and oncogenesis. The biological consequences of Icmt inhibition strongly implicate the enzyme as a potential therapeutic target for cancer and provide a compelling rationale for developing specific Icmt inhibitors as anti-cancer agents. We report here the systematic modification of the known Icmt inhibitor cysmethynil to give an analog 15 with greatly improved solubility and PAMPA permeability which was achieved with concurrent gains in Icmt inhibitory and cell-based antiproliferative activities. The modifications involved replacing the amide side chain of cysmethynil with a tertiary amine, and introducing an aminopyrimidine ring in place of m-tolyl. The presence of the weakly basic and polar aminopyrimidine ring contributed significantly to the potency and drug-like profile of the final compound.

Duke Scholars

Published In

Eur J Med Chem

DOI

EISSN

1768-3254

Publication Date

May 2013

Volume

63

Start / End Page

378 / 386

Location

France

Related Subject Headings

  • Pyrimidines
  • Protein Methyltransferases
  • Molecular Structure
  • Medicinal & Biomolecular Chemistry
  • Indoles
  • Humans
  • Hep G2 Cells
  • Enzyme Inhibitors
  • Dose-Response Relationship, Drug
  • Cell Survival
 

Citation

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MLA
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Ramanujulu, P. M., Yang, T., Yap, S.-Q., Wong, F.-C., Casey, P. J., Wang, M., & Go, M.-L. (2013). Functionalized indoleamines as potent, drug-like inhibitors of isoprenylcysteine carboxyl methyltransferase (Icmt). Eur J Med Chem, 63, 378–386. https://doi.org/10.1016/j.ejmech.2013.02.007
Ramanujulu, Pondy M., Tianming Yang, Siew-Qi Yap, Fui-Chung Wong, Patrick J. Casey, Mei Wang, and Mei-Lin Go. “Functionalized indoleamines as potent, drug-like inhibitors of isoprenylcysteine carboxyl methyltransferase (Icmt).Eur J Med Chem 63 (May 2013): 378–86. https://doi.org/10.1016/j.ejmech.2013.02.007.
Ramanujulu PM, Yang T, Yap S-Q, Wong F-C, Casey PJ, Wang M, et al. Functionalized indoleamines as potent, drug-like inhibitors of isoprenylcysteine carboxyl methyltransferase (Icmt). Eur J Med Chem. 2013 May;63:378–86.
Ramanujulu, Pondy M., et al. “Functionalized indoleamines as potent, drug-like inhibitors of isoprenylcysteine carboxyl methyltransferase (Icmt).Eur J Med Chem, vol. 63, May 2013, pp. 378–86. Pubmed, doi:10.1016/j.ejmech.2013.02.007.
Ramanujulu PM, Yang T, Yap S-Q, Wong F-C, Casey PJ, Wang M, Go M-L. Functionalized indoleamines as potent, drug-like inhibitors of isoprenylcysteine carboxyl methyltransferase (Icmt). Eur J Med Chem. 2013 May;63:378–386.
Journal cover image

Published In

Eur J Med Chem

DOI

EISSN

1768-3254

Publication Date

May 2013

Volume

63

Start / End Page

378 / 386

Location

France

Related Subject Headings

  • Pyrimidines
  • Protein Methyltransferases
  • Molecular Structure
  • Medicinal & Biomolecular Chemistry
  • Indoles
  • Humans
  • Hep G2 Cells
  • Enzyme Inhibitors
  • Dose-Response Relationship, Drug
  • Cell Survival