Isoprenyl carboxyl methyltransferase inhibitors: a brief review including recent patents

Abstract

Among the enzymes involved in the post-translational modification of Ras, isoprenyl carboxyl methyltransferase (ICMT) has been explored by a number of researchers as a significant enzyme controlling the activation of Ras. Indeed, inhibition of ICMT exhibited promising anti-cancer activity against various cancer cell lines. This paper reviews patents and research articles published between 2009 and 2016 that reported inhibitors of ICMT as potential chemotherapeutic agents targeting Ras-induced growth factor signaling. Since ICMT inhibitors can modulate Ras signaling pathway, it might be possible to develop a new class of anti-cancer drugs targeting Ras-related cancers. Researchers have discovered indole-based small-molecular ICMT inhibitors through high-throughput screening. Researchers at Duke University identified a prototypical inhibitor, cysmethynil. At Singapore University, Ramanujulu and his colleagues patented more potent compounds by optimizing cysmethynil. In addition, Rodriguez and Stevenson at Universidad Complutense De Madrid and Cancer Therapeutics CRC PTY Ltd., respectively, have developed inhibitors based on formulas other than the indole base. However, further optimization of chemicals targeted to functional groups is needed to improve the characteristics of ICMT inhibitors related to their application as drugs, such as solubility, effectiveness, and safety, to facilitate clinical use.

Keywords: Cancer; Cysmethynil; ICMT inhibitor; Methylation; Ras.

Fig. 1

Schematic diagram of the RAS/ICMT regulatory process in a growth factor-inducing signaling cascade. FTase farnesyltransferase, RCE1 Ras-converting CAAX endopeptidase 1, ICMT isoprenylcysteine methyltransferase, AdoMet S-adenosyl-l-methionine, AdoHcy S-adenosyl-l-homocysteine, GF growth factor

Fig. 2

Chemical structures of ICMT inhibitors synthesized by Gibbs (Purdue Research Foundation). a Amide-modified farnesyl-cysteine analogs. b Subsequent AMFC library

Fig. 2

Chemical structures of ICMT inhibitors synthesized by Gibbs (Purdue Research Foundation). a Amide-modified farnesyl-cysteine analogs. b Subsequent AMFC library

Fig. 3

Indole-based small-molecule inhibitors of ICMT developed by Casey (Duke University)

Fig. 3

Indole-based small-molecule inhibitors of ICMT developed by Casey (Duke University)

Fig. 3

Indole-based small-molecule inhibitors of ICMT developed by Casey (Duke University)

Fig. 4

ICMT inhibitors developed by Jo Lene Leow (National University of Singapore). a Variation at R1. b Variation at R2. c Variation at R3-tertiary amides. d Variation at R3-other than tertiary amides. e Variation at R3-amines. f Variation at R1 and R2 with R3=amino

Fig. 4

ICMT inhibitors developed by Jo Lene Leow (National University of Singapore). a Variation at R1. b Variation at R2. c Variation at R3-tertiary amides. d Variation at R3-other than tertiary amides. e Variation at R3-amines. f Variation at R1 and R2 with R3=amino

Fig. 4

ICMT inhibitors developed by Jo Lene Leow (National University of Singapore). a Variation at R1. b Variation at R2. c Variation at R3-tertiary amides. d Variation at R3-other than tertiary amides. e Variation at R3-amines. f Variation at R1 and R2 with R3=amino

Fig. 5

ICMT inhibitors developed by Ramanujulu (National University of Singapore). a Small-molecule ICMT inhibitors based on indole. b Small-molecule ICMT inhibitors based on tetrahydrocarbolines

Fig. 5

ICMT inhibitors developed by Ramanujulu (National University of Singapore). a Small-molecule ICMT inhibitors based on indole. b Small-molecule ICMT inhibitors based on tetrahydrocarbolines

Fig. 6

Formulas of ICMT inhibitors developed by Rodriguez (Universidad Complutense De Madrid)

Fig. 7

Pyrazin-2-amine formulas and ICMT inhibitor developed by Stevenson (Cancer Therapeutics CRC PTY Ltd)