SAR103168: a tyrosine kinase inhibitor with therapeutic potential in myeloid leukemias.

SAR103168, a tyrosine kinase inhibitor of the pyrido [2,3-d] pyridimidine subclass, inhibited the kinase activities of the entire Src kinase family, Abl kinase, angiogenic receptor kinases (vascular endothelial growth factor receptor [VEGFR] 1 and 2), Tie2, platelet derived growth factor (PDGF), fibroblast growth factor receptor (FGFR) 1 and 3, and epidermal growth factor receptor (EGFR). SAR103168 was a potent Src inhibitor, with 50% inhibitory concentration (IC50) = 0.65 ± 0.02 nM (at 100 µM ATP), targeting the auto-phosphorylation of the kinase domain (Src(260-535)) and activity of the phosphorylated kinase. Phosphorylation of Src, Lyn and Src downstream signaling pathways (PYK2, P-130CAS, FAK, JNK and MAPK) were inhibited in a dose-dependent manner. SAR103168 inhibited the phosphorylation of STAT5 in KG1 cells and fresh cells from patients with acute myeloid leukemia (AML). SAR103168 inhibited proliferation and induced apoptosis in acute and chronic myeloid leukemic cells at nanomolar IC50. SAR103168 induced anti-proliferation of leukemic progenitors (CFU-L) from 29 patients with AML, and > 85% of AML patient samples were sensitive to SAR103168. These antagonist activities of SAR103168 were independent of FLT3 expression. SAR103168 treatment was effective in 50% of high-risk patient samples carrying chromosome 7 abnormalities or complex rearrangement. SAR103168 administration (intravenous or oral) impaired tumor growth and induced tumor regression in animals bearing human AML leukemic cells, correlating with potent inhibition of Src downstream signaling pathways in AML tumors. SAR103168 showed potent anti-tumor activity in SCID (severe combined immunodeficiency) mice bearing AML (KG1, EOL-1, Kasumi-1, CTV1) and chronic myeloid leukemia (CML) (K562) tumors. The combination of cytarabine and SAR103168 showed synergistic activity in AML and CML tumor models. These results highlight the therapeutic potential of SAR103168 in myeloid leukemias and support the rationale for clinical investigations.

N-heterocyclic carbene-amine Pt(II) complexes, a new chemical space for the development of platinum-based anticancer drugs.

N-Heterocyclic carbene (NHC) platinum complexes have been highlighted as a promising and original platform for building new cytotoxic drugs of the cisplatin series. Mixed NHC-amine Pt(II) complexes have been prepared via a facile and modular two step sequence leading to trans-configured square planar species. They have been characterized by spectroscopic methods and X-ray diffraction studies. Their efficiency against both cisplatin sensitive (CEM and H460) and resistant (A2780/DDP, CH1/DDP, and SK-OV-3) cell lines has been demonstrated by in vitro experiments.

Sigma receptor ligands: applications in inflammation and oncology.

Sigma (sigma) receptors were initially proposed as a subtype of opiate receptors, and bind several psychoactive compounds. They are classified into sigma 1 (sigma1) and sigma 2 (sigma2) subtypes. The characterization of these subunits, and the discovery of new specific sigma receptor ligands, demonstrated that sigma receptors belong to a specific entity distinct from opiate receptors. Radioligand-binding data have recently demonstrated that the sigma1 subtype is related to a sterol isomerase, which is involved in the cholesterol biosynthesis pathway, and also to another protein of unknown function, SRBP2 (SR-31747 binding-protein 2), which shares a high homology with this enzyme. This complex group of proteins also binds molecules devoid of central effect, which demonstrate potent anti-inflammatory properties, and so are potentially useful in pathologies where pro-inflammatory cytokines are involved, particularly rheumatoid arthritis, Crohn's disease or psoriasis. In addition, the two sigma receptor subtypes and their two related proteins are also expressed on tumor cells, where they could be of prognostic relevance, and their ligands could potentially be used in the detection and targeting of tumors.

SR31747A: a peripheral sigma ligand with potent antitumor activities.

SR31747A is currently being evaluated in phase IIb clinical trials for prostate cancer treatment. The molecule is a peripheral sigma ligand that binds four proteins in human cells, i.e. SRBP-1, sigma-2, HSI and its relative SRBP-2. SR31747A is a dual agent with both immunomodulatory and antiproliferative activities. The molecule blocks proliferation of human and mouse lymphocytes, modulates the expression of pro- and anti-inflammatory cytokines, and was shown to protect animals in vivo against acute and chronic inflammatory conditions such as acute graft-versus-host reaction, lethality induced by staphylococcal enterotoxin B and lipopolysaccharide or rheumatoid arthritis. Besides these immunomodulatory activities, the molecule also inhibits the proliferation of various tumor cell lines in vitro in a time- and concentration-dependent manner. In vivo, SR31747A has potent antitumoral activity as demonstrated against mammary and prostatic tumoral cell lines injected into nude mice, where both tumor incidence and growth were decreased by more than 40% following daily SR31747A treatment at 25 mg/kg i.p. The recent literature on SR31747A in cancer is reviewed here. We focus specifically on preclinical data obtained in vivo and on studies aimed at deciphering the mode of action of the molecule.

Ligands of the peripheral benzodiazepine receptor have therapeutic effects in pneumopathies in vivo.

In this study, we documented the effects of different peripheral benzodiazepine receptor (PBR) ligands: PK 11195, Ro5-4864 and the newly described SSR 180575 on the development of pulmonary inflammation in vivo. To this aim, we used MRL/lpr mice that develop pathological signs similar to the human lupus erythematosus (LE) signs. We found that a chronic treatment (at 3 mg/kg per i.p. for 30 days) with PBR ligands had a significant beneficial therapeutic action and decreased the inflammatory pulmonary responses and alveolitis onset. When analyzing PBR expression in inflamed tissues, we observed that in addition to the infiltrated leukocytes, PBR was expressed in the bronchial epithelium, and especially we evidenced for the first time that PBR in expressed in Clara cells. Interestingly, we observed that PBR expression in those cells was reduced when MRL/lpr mice developed the pathology and restored upon PBR ligand treatment. These original findings support a role of PBR in pulmonary inflammatory process and suggest new therapeutic applications in auto immune disorders for specific potent PBR ligands.

Involvement of the peripheral benzodiazepine receptor in the development of cutaneous pathology in Mrl/Lpr mice.

Mrl/Lpr mice develop inflammatory pathologies similar to human lupus erythematosus (LE). In that model, we showed a protective effect of different peripheral benzodiazepine receptor (PBR) ligands: PK 11195, Ro5-4864 and the newly described SSR180575 on the development of the cutaneous lesions. Specifically, we evidenced that a chronic treatment at 3 mg/kg per i.p. for 30 days prevented acanthosis, hyperkeratosis and generation of dermal infiltrates as compared with control untreated mice. In addition, using a specific polyclonal anti mouse PBR antibody, we characterized PBR expression in the skin lesions, and we observed that PBR expression in the epidermal component was increased when Mrl/Lpr mice developed the pathology and diminished upon PBR ligand treatment. PBR expression modulation together with the protective effects of its ligands further reinforce the role that PBR may play in the regulation of inflammation processes. Provided the exact mechanism of action that accounts for PBR action in that process is elucidated, these data support new therapeutic applications for specific potent PBR ligands.

SSR125329A, a high affinity sigma receptor ligand with potent anti-inflammatory properties.

SSR125329A ([(Z)-3-(4-Adamantan-2-yl-3,5-dichloro-phenyl)-allyl]-cyclohexyl-ethyl-amine) is a new ligand exhibiting high affinity for sigma(1) and sigma(2) receptors and for the human Delta8-Delta7-sterol isomerase. Here we show that this molecule has potent immunoregulatory properties both in vitro and in vivo. SSR125329A inhibited staphylococcal enterotoxin B-induced mouse splenocyte proliferation in vitro, whereas in vivo it enhanced lipopolysaccharide-induced systemic release of interleukin-10 while simultaneously inhibiting tumor necrosis factor-alpha (TNF-alpha) synthesis. It also prevented graft-versus-host disease in B6D2F1 mice and protected Mrl/lpr mice against the development of its spontaneous rheumatoid-like syndrome. There is high interplay of pro- and anti-inflammatory cytokines in inflammatory processes, particularly in human rheumatoid arthritis. The results of this study provide substantial evidence that sigma receptor ligands may represent a new effective approach for rheumatoid arthritis treatment.

Involvement of the peripheral benzodiazepine receptor in the development of rheumatoid arthritis in Mrl/lpr mice.

In this study, the effects of different peripheral benzodiazapine receptor ligands: PK 11195 [1-(2-chloro-phenyl)-N-methyl-N-(1-methylpropyl)-1-isoquinoline carboxamide], Ro5-4864 [7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one] and the newly described SSR 180575 (7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridozine[4,5-b] indole-1-acetamide) were analysed on the progression and severity of rheumatoid arthritis in vivo in the Mrl/lpr mice model, following chronic treatment (at 3 mg/kg, i.p. for 30 days). We found that peripheral benzodiazepine receptor ligands have significant beneficial therapeutic action on the development of spontaneous rheumatoid arthritis-like signs. Concomitantly, we mapped immunoreactive peripheral benzodiazepine receptor in inflamed tissues, and we observed that in addition to the infiltrated leukocytes, peripheral benzodiazepine receptor was expressed in synovial membranes, at the cartilage pannus junction and in chondrocytes. Interestingly, we observed that peripheral benzodiazepine receptor expression in chondrocytes was reduced when Mrl/lpr mice developed the pathology and restored upon peripheral benzodiazepine receptor ligand treatment. Altogether, our data provide further evidence of a role played by peripheral benzodiazepine receptor in the regulation of inflammation processes and support new therapeutic applications for specific potent peripheral benzodiazepine receptor ligands.