Abdelazize Laoui

Telomerase : A therapeutic target for the third millennium?

Telomerase offers the potential opportunity to control cell proliferation by interfering with a totally new and unique biological process which is cell senescence. The aim of this review is to impartially present the state of the art in telomerase with the pros and the cons of the current scientific situation of this fast-growing and fascinating topic for answering the key question asked by experimental and medical oncologists: Will telomerase be a therapeutic target for the third millenium? The most convincing argument (which is a scientifically documented one) for going ahead with this target is obviously the strong correlation existing between the level and frequency of telomerase expression and the malignant properties of tumors. This has been now largely documented in established tumor cell lines and fresh tumor samples obtained from patients. Noteworthy is the very important difference of telomerase expression between malignant and normal tissues. This difference is much higher than those observed for classical enzymatic targets of chemotherapy such as thymidylate synthetase, dihydrofolate reductase and topoisomerases. If this translates to the clinical situation, telomerase inhibitors might display a good selectivity for tumor cells with a minimal toxicity for normal tissues. The most appealing criticism (which is still purely speculative) is obviously the clinical relevance of inhibiting telomerase in cancer patients. According to the paradigm currently proposed for telomeres and telomerases, it can be predicted that telomerase inhibition will not affect a tumor until its telomeres reach the critical size for entering senescence. This means that during anti-telomerase therapy, the tumor cells will continue grow undergoing 20-30 divisions until the telomeres reach a critical size leading to tumor senescence. Does this make sense, especially in patients with advanced tumors at the beginning of the therapy? Ultimately, the definitive answer to the question will not come from intellectual speculation but from the properties of telomerase inhibitors, first in tumor bearing animals, then finally in cancer patients! Several institutions are very active in the development of telomerase inhibitors. Different stategies are used: direct inhibition of telomerase, interference with telomeres (G quartets), interaction with other proteins involved in the regulation of telomerase and telomeres.

DIVSEL and COMPLIB - Strategies for the Design and Comparison of Combinatorial Libraries using Pharmacophoric Descriptors

Screening synthetic combinatorial libraries may facilitate rapid drug lead discovery by substantially increasing the number of molecules tested. Drug discovery efficiency and productivity can be further improved by designing libraries to maximize their molecular diversity or by comparing them to existing collections of compounds and/or libraries to select those that complement the properties already well represented. In this paper we describe two strategies to aid in the design and comparison of combinatorial libraries. The methods employ multi-pharmacophore three-dimensional (3D) descriptors in combination with two recent proposals for dissimilarity-based compound selection and library comparison. This method allows the design to be performed in product space and library comparison to consider all pair-wise intermolecular contributions to the diversity.

Structural Requirements to Obtain Potent CAXX Mimic P21-Ras-Farnesyltransferase Inhibitors

Famesyltransferase (FTase) farnesylates p21ras on the Cys residue of the C-terminal consensus sequence referred to as a CAAX box (where C is cysteine, A is an aliphatic amino acid and X is any amino acid). This modification is required for membrane association and function of both normal and cell transforming ras activity. Transformed ras proteins are implicated in a number of human cancers including colon, pancreatic and lung carcinomas. Therefore selective inhibition of FTase could lead to a new class of potent and specific anticancer agents.