Tasquinimod triggers an early change in the polarization of tumor associated macrophages in the tumor microenvironment.

Background: Tasquinimod (a quinoline-3-carboxyamide) is a small molecule immunotherapy with demonstrated effects on the tumor microenvironment (TME) involving immunomodulation, anti-angiogenesis and inhibition of metastasis. A target molecule of tasquinimod is the inflammatory protein S100A9 which has been shown to affect the accumulation and function of suppressive myeloid cell subsets in tumors. Given the major impact of myeloid cells to the tumor microenvironment, manipulation of this cell compartment is a desirable goal in cancer therapeutics.

Functional coupling of FcgammaRI to nicotinamide adenine dinucleotide phosphate (reduced form) oxidative burst and immune complex trafficking requires the activation of phospholipase D1.

Immunoglobulin G (IgG) receptors (FcgammaRs) on myeloid cells are responsible for the internalization of immune complexes. Activation of the oxidase burst is an important component of the integrated cellular response mediated by Fc receptors. Previous work has demonstrated that, in interferon-gamma-primed U937 cells, the high-affinity receptor for IgG, FcgammaRI, is coupled to a novel intracellular signaling pathway that involves the sequential activation of phospholipase D (PLD), sphingosine kinase, and calcium transients.

Investigation of the structural parameters involved in the delta-opioid selectivity of several families of opioid peptides.

Three series of highly delta-opioid selective peptides are now available, and each family is used as template to investigate the structural parameters involved in delta-receptor recognition and in the modulation of the selectivity of the parent peptide. The first series includes cyclic derivatives such as Tyr-D-Pen-Gly-Phe-D-Pen(DPDPE) and Tyr-D-Pen-Gly-Phe-Pen(DPLPE); the second are the synthetic linear constrained peptides [Tyr-D-Ser(OtBu)-Gly-Phe-Leu-Thr(DSTBULET), Tyr-D-Ser(OtBu)-Gly-Phe-Leu-Thr (OtBu)(BUBU) and especially Tyr-D-Cys(StBu)-Gly-Phe-Leu-Thr(OtBu) (BUBUC)] and the last one the natural peptides [Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2 (deltorphin or dermenkephalin) and Tyr-D-Ala-Phe-Asp-Val-Val-GlyNH2 ([D-Ala2] deltorphin I)]. In the present study, the possibly of transposing some of the decisive factors of delta-selectivity evidenced in the two other families, to the linear constrained peptides series was examined.

Exploration of neutral endopeptidase active site by a series of new thiol-containing inhibitors.

With the aim of characterizing the active site of the neutral endopeptidase [EC 3.4.24.

Potent and systemically active aminopeptidase N inhibitors designed from active-site investigation.

Derivatives of amino acids bearing various zinc-coordinating moieties (SH, COOH, CONHOH, and PO3H2) were synthesized and tested for their ability to inhibit aminopeptidase N (APN). Among them, beta-amino thiols were found to be the most efficient with IC50's in the 11-50 nM range. These results suggest that the S1 subsite of APN is a deep but not very large hydrophobic pocket, optimally fitting side chains of moderate bulk endowed with some degree of freedom.