IMPDH inhibition activates TLR-VCAM1 pathway and suppresses the development of MLL-fusion leukemia.

Inosine monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme in de novo guanine nucleotide synthesis pathway. Although IMPDH inhibitors are widely used as effective immunosuppressants, their antitumor effects have not been proven in the clinical setting. Here, we found that acute myeloid leukemias (AMLs) with MLL-fusions are susceptible to IMPDH inhibitors in vitro.

Results of a Phase 1/2a dose-escalation study of FF-10501-01, an IMPDH inhibitor, in patients with acute myeloid leukemia or myelodysplastic syndromes.

FF-10501-01 potently inhibits inosine-5-monophosphate dehydrogenase (IMPDH), inducing anti-proliferative and pro-apoptotic effects in acute myeloid leukemia (AML) human cell lines resistant to hypomethylating agents. In this Phase 1/2a study, Phase 1 enrolled 38 patients with relapsed/refractory AML ( = 28) or myelodysplastic syndromes (MDS/CMML,  = 10) to receive FF-10501 oral doses 50-500 mg/m BID for 14 or 21 days out of each 28-day cycle. Fifteen additional patients with HMA-resistant MDS/CMML (Phase 2a) were treated at 400 mg/m BID for 21 days.

FF-10502, an Antimetabolite with Novel Activity on Dormant Cells, Is Superior to Gemcitabine for Targeting Pancreatic Cancer Cells.

In this paper, we report that 1-(2-deoxy-2-fluoro-4-thio--d-arabinofuranosyl) cytosine (FF-10502), a pyrimidine nucleoside antimetabolite with a chemical structure similar to gemcitabine, shows beneficial anticancer activity via a novel mechanism of action on dormant cells. The growth inhibition of pancreatic cancer cell lines by FF-10502 (IC, 60-330 nM) was moderately weaker than that by gemcitabine in vitro. In contrast, an in vivo orthotopic implantation model in mice with established human pancreatic cancer cell line, SUIT-2, revealed no mortality with FF-10502 intravenous treatment, which was related to regression of implanted tumor and little metastasis, whereas 75% of the mice treated with gemcitabine died by day 128.

Molecular targeting of inosine-5'-monophosphate dehydrogenase by FF-10501 promotes erythropoiesis via ROS/MAPK pathway.

One of the major symptoms of myelodysplastic syndromes (MDS) is severe cytopenia. Despite cytokine therapies, such as erythropoiesis-stimulating agents, many patients still require blood transfusions, and the development of new therapeutic approaches is needed. In this work, we studied the effects of the inosine-5'-monophosphate (IMP) dehydrogenase (IMPDH) inhibitor FF-10501 on erythropoiesis of human hematopoietic cells.

Preclinical activity of FF-10501-01, a novel inosine-5'-monophosphate dehydrogenase inhibitor, in acute myeloid leukemia.

Background: FF-10501-01 is a selective inosine monophosphate dehydrogenase (IMPDH) inhibitor that has shown activity in cancer cell lines. We studied whether FF-10501-01 is effective in targeting a variety of hypomethylating agent (HMA)-sensitive and -resistant acute myelogenous leukemia (AML) cell lines.

Methods: We treated multiple cell lines (including HMA-resistant cells) with FF-10501-01 and analyzed proliferation, apoptosis, and cell cycle status.

Lack of cross-resistance to FF-10501, an inhibitor of inosine-5'-monophosphate dehydrogenase, in azacitidine-resistant cell lines selected from SKM-1 and MOLM-13 leukemia cell lines.

Resistance to azacitidine is a major issue in the treatments of myelodysplastic syndrome and acute myeloid leukemia, and previous studies suggest that changes in drug metabolism are involved in the resistance. Therefore, drugs with mechanisms resistant or alternative to such metabolic changes have been desired for the treatment of resistant disease. We generated azacitidine-resistant cells derived from SKM-1 and MOLM-13 leukemia cell lines in vitro, analyzed the mechanisms, and examined the impact on the efficacy of other antimetabolic drugs.

Involvement of central cannabinoid CB2 receptor in reducing mechanical allodynia in a mouse model of neuropathic pain.

We sought to examine the involvement of central cannabinoid CB2 receptor activation in modulating mechanical allodynia in a mouse model of neuropathic pain. JWH133 was demonstrated to be a selective cannabinoid CB2 receptor agonist in mice, reducing forskolin-stimulated cAMP production in CHO cells expressing mouse cannabinoid CB2 and cannabinoid CB1 receptors with EC50 values of 63 nM and 2500 nM, respectively. Intrathecal administration of JWH133 (50 and 100 nmol/mouse) significantly reversed partial sciatic nerve ligation-induced mechanical allodynia in mice at 0.

Immunoglobulin E-independent activation of mast cell is mediated by Mrg receptors.

Mast cells play a central role in inflammatory and allergic reactions by releasing inflammatory mediators through two main pathways, immunoglobulin E-dependent and -independent activation. In the latter, mast cells are activated by a diverse range of basic molecules, including peptides and amines such as substance P, neuropeptide Y, and compound 48/80. These secretagogues are thought to activate the G proteins in mast cells through a receptor-independent mechanism.

Involvement of cannabinoid CB(2) receptor-mediated response and efficacy of cannabinoid CB(2) receptor inverse agonist, JTE-907, in cutaneous inflammation in mice.

Involvement of cannabinoid CB(2) receptor and effect of cannabinoid CB(2) receptor antagonist/inverse agonists on cutaneous inflammation were investigated. Mice ears topically exposed to an ether-linked analogue of 2-arachidonoylglycerol (2-AG-E) or selective cannabinoid CB(2) receptor agonist, {4-[4-(1,1-dimethylheptyl)-2,6-dimethoxy-phenyl]-6.6-dimethyl-bicyclo[3.

JTP-27536 [(+)-1,3-dihydroxy-2-hydroxymethylpropyl-2-ammonium 2-[(R)-3-cyclo-hexyl-1-phenylpropyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylate monohydrate], a novel inhibitor of immunoglobulins and interleukin-5 with anti-inflammatory properties in mouse allergic dermatitis model.

We report a novel synthetic compound JTP-27536 [(+)-1,3-dihydroxy-2-hydroxymethylpropyl-2-ammonium 2-[(R)-3-cyclohexyl-1-phenylpropyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylate monohydrate] as an inhibitor of immunoglobulins (Igs) and interleukin (IL)-5 production in vitro and in vivo. JTP-27536 inhibited IgE production in mouse and human B cells with IC50 values of 2.5 and 2.

Comparative study of glucocorticoids, cyclosporine A, and JTE-607 [(-)-Ethyl-N[3,5-dichloro-2-hydroxy-4-[2-(4-methylpiperazin-1-yl)ethoxy]benzoyl]-L-phenylalaninate dihydrochloride] in a mouse septic shock model.

Actions of glucocorticoids, cyclosporine A, and JTE-607 [(-)-ethyl-N-[3,5-dichloro-2-hydroxy-4-[2-(4-methylpiperazin-1-yl)ethoxy]benzoyl]-L-phenylalaninate dihydrochloride], a proinflammatory cytokine inhibitor that does not inhibit interleukin (IL)-2 or interferon-gamma, were compared in a mouse septic shock model induced by cecal ligation and puncture (CLP). CLP caused elevation of macrophage inflammatory protein (MIP)-2 in lung, and MIP-2 and IL-6 in plasma and peritoneal fluid, reaching a peak 4 to 8 h after CLP. Myeloperoxidase (MPO) activity in lung increased and reached a peak 8 to 12 h after CLP.

Induction of megakaryocytopoiesis and thrombocytopoiesis by JTZ-132, a novel small molecule with thrombopoietin mimetic activities.

We report in this paper that a novel small molecule, JTZ-132, induced growth and differentiation of megakaryocytic progenitor cells and improved thrombocytopenia in myelosuppressed mice. JTZ-132 stimulated proliferation of UT-7/TPO cells, a cell line highly sensitive to thrombopoietin (TPO), and exhibited full efficacy comparable to TPO with an approximate EC(50) (median effective concentration) value of 0.43 microM, whereas little proliferation was observed in a TPO-insensitive cell line, UT-7/EPO, and human carcinoma cell line, HCT116.

Prior burn insult induces lethal acute lung injury in endotoxemic mice: effects of cytokine inhibition.

Many patients who experience surgical stress, including burn injury, become susceptible to severe sepsis and septic organ dysfunction, which remains the primary contributor to morbidity and mortality in burn patients. In the present study, we developed a murine model of burn-primed sublethal endotoxemia by producing a 15% BSA full-thickness burn on the dorsum of BALB/c mice under ether anesthesia and administering 10 mg/kg of LPS intravenously on day 11 to model endotoxemia. The prior burn injury in this model induced two-peaked production of cytokines, TNF-alpha, and macrophage inflammatory protein-2 at 2 and 12 h after LPS administration, and it was associated with increased mortality.

Neutralization of IFN-inducible protein 10/CXCL10 exacerbates experimental autoimmune encephalomyelitis.

We examined the effect of a monoclonal antibody (mAb) against interferon (IFN)-inducible protein 10 (IP-10)/CXCL10 on the development of experimental autoimmune encephalomyelitis (EAE) in rats induced by injecting xenogeneic brain homogenates into footpads. Treatment with neutralizing mAb against CXCL10 exacerbated EAE with increased infiltrating CD4+ cells in the central nervous system. Furthermore, the exacerbation by the mAb treatment was accompanied by less enlarged draining popliteal lymph nodes (LN) in parallel with cell number compared with those of EAE rats treated with control mAb, whereas other lymphoid organs such as the spleen and thymus were not significantly different between rats treated with anti-CXCL10 and the control mAb.