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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. We also showed that alternate‐day administration of IMPDH inhibitors suppressed the development of MLL‐AF9‐driven AML in vivo without having a devastating effect on immune function. Mechanistically, IMPDH inhibition induced overactivation of Toll‐like receptor (TLR)‐TRAF6‐NF‐κB signaling and upregulation of an adhesion molecule VCAM1, which contribute to the antileukemia effect of IMPDH inhibitors. Consequently, combined treatment with IMPDH inhibitors and the TLR1/2 agonist effectively inhibited the development of MLL‐fusion AML. These findings provide a rational basis for clinical testing of IMPDH inhibitors against MLL‐fusion AMLs and potentially other aggressive tumors with active TLR signaling. Synopsis: This study describes the potent antileukemia effect of IMPDH inhibitors on MLL‐fusion leukemias, which is partly mediated by the overactivation of TLR‐NF‐kB‐Vcam1 pathway. MLL‐fusion leukemias are particularly susceptible to IMPDH inhibition.An alternate‐day administration of IMPDH inhibitors effectively suppresses MLL‐AF9‐driven leukemogenesis in vivo through myeloid differentiation without any devastating effect on immune function.IMPDH inhibition results in activation of TLR pathway and Vcam1 upregulation in MLL‐fusion leukemia cells.Combined treatment with IMPDH inhibitors and the TLR1/2 agonist shows potent antileukemia effects in vivo. [ABSTRACT FROM AUTHOR]

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. We also assessed the effect of pharmacological modulation with cytokine synthesis inhibitors prednisolone and JTE-607 and found that pretreatment with them attenuated later cytokine production and decreased mortality after LPS administration. We speculate that the prior burn injury primed the mice for the secondary insult via cytokine production. These results also suggested that an anticytokine strategy might serve as a novel prophylactic therapy for septic organ dysfunction in burn-primed patients. two-hit phenomenon; priming; systemic inflammatory response syndrome; chemokine; JTE-607

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 (n = 28) or myelodysplastic syndromes (MDS/CMML, n = 10) to receive FF-10501 oral doses 50–500 mg/m2 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/m2 BID for 21 days. Most Phase 1 adverse events were disease-related and low-grade. 3 of 19 (16%) evaluable AML patients achieved partial remission (31, 7, and 5 months). 2 of 20 (10%) evaluable MDS/CMML patients (Phase 1 and 2a) attained marrow complete remission, one continuing treatment for 17 months. While FF-10501-01 demonstrated clinical activity and target inhibition in heavily pretreated patients with AML and MDS/CMML, increased mucositis events led to Phase 2a closure (ClinTrials.gov#NCT02193958). [ABSTRACT FROM AUTHOR]

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. Differentiation of K562 chronic myeloid leukemia cells to an erythroid lineage was promoted by FF-10501 in a dose-dependent manner. Interestingly, we found that metabolic conversion of IMP to hypoxanthine leads to elevation of reactive oxygen species (ROS). The differentiative effects of FF-10501 were abolished by the ROS scavenger dimethylthiourea or the p38 MAPK inhibitor SB203580. Furthermore, FF-10501 promoted erythropoiesis from CD34+hematopoietic stem/progenitor cells, accompanied with ROS accumulation, while high-dose FF-10501 mainly showed cytotoxic effects. These findings denote the potential of IMPDH inhibition therapy with FF-10501 in amelioration of anemia in MDS patients. [ABSTRACT FROM AUTHOR]

Abstract: 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 0.5 h after administration. In contrast, systemic (intraperitoneal) or local (injected to the dorsal surface of the hindpaw) administration of JWH133 (100 nmol/mouse) was ineffective. Furthermore, the analgesic effects of intrathecal JWH133 (100 nmol/mouse) were absent in cannabinoid CB2 receptor knockout mice. These results suggest that the activation of central, but not peripheral, cannabinoid CB2 receptors play an important role in reducing mechanical allodynia in a mouse model of neuropathic pain. [Copyright &y& Elsevier]

Abstract: Involvement of cannabinoid CB2 receptor and effect of cannabinoid CB2 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 CB2 receptor agonist, {4-[4-(1,1-dimethylheptyl)-2,6-dimethoxy-phenyl]-6.6-dimethyl-bicyclo[3.1.1]hept-2-en-2-yl}-methanol (HU-308), had early and late ear swelling (0–24 h and 1–8 days after exposure, respectively). Both types of responses induced by 2-AG-E were significantly suppressed by oral administration of cannabinoid CB2 receptor antagonist/inverse agonists, [N-(benzo[1,3]dioxol-5-ylmethyl)-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxamide] (JTE-907) and {N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2yl]5-(4-chloro-3-methyl-phenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide}} (SR144528). In contrast, JTE-907 did not affect arachidonic acid-induced swelling. Orally administered JTE-907 (0.1–10 mg/kg) and SR144528 (1 mg/kg) also produced significant inhibition of dinitrofluorobenzene-induced ear swelling, with increased cannabinoid CB2 receptor mRNA expression observed in the inflamed ear. These results suggest that cannabinoid CB2 receptor is partially involved in local inflammatory responses and cannabinoid CB2 receptor antagonist/inverse agonist has beneficial effects on ear swelling. [Copyright &y& Elsevier]

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. Acute treatment (subcutaneous injections 1 h before and 2 h after CLP) of mice with JTE-607 and methylprednisolone showed significant inhibition of elevated cytokine levels and MPO activity, plus increased survival rate. Similar treatment with cyclosporine A and prednisolone was ineffective. Chronic treatment (subcutaneous injection for seven consecutive days before CLP) of mice with JTE-607 also showed an inhibitory effect on cytokine production, MPO activity and mortality. In contrast, chronic treatment with cyclosporine A and prednisolone did not inhibit cytokine production or MPO activity, but rather exacerbated mortality. These results indicate that JTE-607 has protective effect on mouse mortality induced by CLP, correlating with inhibition of proinflammatory cytokines, whereas the immunosuppressants cyclosporine A and prednisolone do not. This suggests that JTE-607, a multiple cytokine inhibitor that does not cause adverse immunosuppression, is useful for treatment of septic shock.