ABSTRACT
The identification of a CDC25 inhibitor to arrest the cell cycle closely followed the discovery of CDC25 by Russell and Nurse in 1986. Recent advances at the preclinical and clinical stages reinforce the rationale to consider CDC25 as a relevant target for a cancer treatment. Here, in order to exemplify recent drug discovery efforts, we present our own experience with various chemical series of CDC25 inhibitors. We discuss how we have progressed and how we are considering the next steps to define the clinical entry points and hopefully complete this target validation to generate a new class of therapeutic agents.
Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , cdc25 Phosphatases/antagonists & inhibitors , Animals , HumansABSTRACT
Oncogenic mutations of the ras gene leading to constitutive activation of downstream effectors have been detected in a wide spectrum of human cancers (pancreas, thyroid, colon, non-small-cell lung cancer). Membrane anchorage of Ras, required for functional activity in signal transduction, is facilitated by post-translational modifications resulting in covalent attachment of a farnesyl group to the cysteine in the C-terminal CAAX motif. This attachment is mediated by farnesyltransferase (FTase). Here, we report a novel FTase inhibitor, BIM-46228, which showed (i) specific inhibition of purified human FTase enzyme, (ii) inhibition of proliferation in vitro in a large spectrum of human tumor cell lines, (iii) inhibition of growth of human tumor xenografts in athymic nude mice treated by per os administration and (iv) the benefits of in vitro combination of its activity with chemotherapy or radiotherapy.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Antineoplastic Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Imidazoles/therapeutic use , Lovastatin/analogs & derivatives , Nitriles/therapeutic use , Peptides/therapeutic use , 3T3 Cells , Animals , Anti-Bacterial Agents/therapeutic use , Antineoplastic Agents, Phytogenic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Blotting, Western , Cell Division , Combined Modality Therapy , Dimethylallyltranstransferase/metabolism , Dose-Response Relationship, Drug , Dose-Response Relationship, Radiation , Farnesyltranstransferase , Female , Genes, ras/genetics , HeLa Cells , Humans , Imidazoles/chemistry , Inhibitory Concentration 50 , Lovastatin/therapeutic use , Mice , Mice, Nude , Models, Chemical , Neoplasm Transplantation , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/radiotherapy , Nitriles/chemistry , Paclitaxel/therapeutic use , Time Factors , Tumor Cells, CulturedABSTRACT
Oncogenic mutations of the ras gene leading to constitutive activation of downstream effectors have been detected in a large spectrum of human cancers (pancreas, thyroid, colon and NSCLC). Membrane anchorage of Ras required for functional activity in signal transduction is facilitated by post-translational modifications resulting in covalent attachment of a farnesyl group to the cysteine in the C-terminal CAAX motif. This attachment is mediated by farnesyltransferase (FTase). Here, we report a novel series of potent FTase inhibitors, where the tetrapeptide CAAX motif has been modified by incorporation of a thiazolidine carboxylic acid moiety followed by reduction of the 1st and 2nd peptide bonds to a secondary and tertiary amine, respectively. The C-terminal carboxylate was converted to esters for improved cellular penetration. These compounds showed specific inhibition of purified human FTase enzyme, inhibition of proliferation in vitro in a large spectrum of human tumor cell lines and inhibition of growth of human tumor xenografts in athymic nude mice. In addition, in regard to a panel of cell lines, using the Compare analysis to determine the Pearson coefficient correlation, the anti-proliferative spectrum of BIM-46068 has been shown to be distinct from the profile of typical chemotherapeutic agents.
