Conception rationnelle et synthèse d'inhibiteurs des phosphatases CDC25 à activité anti-tumorale potentielle

PARIS-BIUP (751062107) / SudocSudocFranceF

A Very Short Route to Enantiomerically Pure Coumarin-Bearing Fluorescent Amino Acids

International audienceNo bulkier than a tryptophan or a tyrosine residue are the fluorescent coumaryl amino acids described. These building blocks can be synthesized rapidly with high enantiomeric purity and introduced readily into a peptidic sequence. Their fluorescence properties allow, for example, the investigation of the cellular localization of labeled peptides through confocal fluorescence microscop

An alternative route to the proline derivative (2S,5R)-5-ethoxycarbonylmethyl-pyrrolidine-2-carboxylic acid from protected glutamic acid

International audienceThe synthesis of (2S,5R)-5-ethoxycarbonylmethyl-pyrrolidine-2-carboxylic acid was achieved in two steps, with an overall yield of 53%. This synthesis used Cbz-Glu-OBzl as the starting material and led to the titled compound with a d.e.>96%

Design, synthesis, and biological evaluation of novel naphthoquinone derivatives with CDC25 phosphatase inhibitory activity.

CDC25 dual-specificity phosphatases are essential key regulators of eukaryotic cell cycle progression and the CDC25A and B isoforms are over-expressed in different tumors and related cancer cell lines. CDC25s are now considered to be interesting targets in the search for novel anticancer agents. We describe new compounds derived from vitamin K3 that inhibit CDC25B activity with IC50 values in the low micromolar range. These naphthoquinone derivatives also display antiproliferative activity on HeLa cells as expected for CDC25 inhibitors and inhibit cell growth in a clonogenic assay at submicromolar concentrations. They increase inhibitory tyrosine 15 phosphorylation of CDK and induce the cleavage of PARP, a hallmark of apoptosis

Site-Specific Antibody Conjugation to Engineered Double Cysteine Residues

Site-specific antibody conjugations generate homogeneous antibody-drug conjugates with high therapeutic index. However, there are limited examples for producing the site-specific conjugates with a drug-to-antibody ratio (DAR) greater than two, especially using engineered cysteines. Based on available Fc structures, we designed and introduced free cysteine residues into various antibody CH2 and CH3 regions to explore and expand this technology. The mutants were generated using site-directed mutagenesis with good yield and properties. Conjugation efficiency and selectivity were screened using PEGylation. The top single cysteine mutants were then selected and combined as double cysteine mutants for expression and further investigation. Thirty-six out of thirty-eight double cysteine mutants display comparable expression with low aggregation similar to the wild-type antibody. PEGylation screening identified seventeen double cysteine mutants with good conjugatability and high selectivity. PEGylation was demonstrated to be a valuable and efficient approach for quickly screening mutants for high selectivity as well as conjugation efficiency. Our work demonstrated the feasibility of generating antibody conjugates with a DAR greater than 3.4 and high site-selectivity using THIOMABTM method. The top single or double cysteine mutants identified can potentially be applied to site-specific antibody conjugation of cytotoxin or other therapeutic agents as a next generation conjugation strategy