5-alpha-reductase

2013年1月5日星期六

Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.

Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.

Bioorg Med Chem Lett. 2012 Sep 15;22(18):5903-8

Authors: Raheem IT, Breslin MJ, Fandozzi C, Fuerst J, Hill N, Huszar S, Kandebo M, Kim SH, Ma B, McGaughey G, Renger JJ, Schreier JD, Sharma S, Smith S, Uslaner J, Yan Y, Coleman PJ, Cox CD

Abstract
We describe the discovery of potent and orally bioavailable tetrahydropyridopyrimidine inhibitors of phosphodiesterase 10A by systematic optimization of a novel HTS lead. Lead compound THPP-1 exhibits nanomolar potencies, excellent pharmacokinetic properties, and a clean off-target profile. It displays in vivo target engagement as measured by increased rat striatal cGMP levels upon oral dosing. It shows dose-dependent efficacy in a key pharmacodynamic assay predictive of antipsychotic activity, the psychostimulant-induced rat hyperlocomotion assay. Further, THPP-1 displays significantly fewer preclinical adverse events in assays measuring prolactin secretion, catalepsy, and weight gain, in contrast to the typical and atypical antipsychotics haloperidol and olanzapine.

PMID: 22892116 [PubMed - indexed for MEDLINE]

ecdysone chir-258 dovitinib

A critical role for p130Cas in the progression of pulmonary hypertension in humans and rodents.

A critical role for p130Cas in the progression of pulmonary hypertension in humans and rodents.

Am J Respir Crit Care Med. 2012 Oct 1;186(7):666-76

Authors: Tu L, De Man FS, Girerd B, Huertas A, Chaumais MC, Lecerf F, Fran�ois C, Perros F, Dorfm�ller P, Fadel E, Montani D, Eddahibi S, Humbert M, Guignabert C

Abstract
RATIONALE: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by pulmonary arterial muscularization due to excessive pulmonary vascular cell proliferation and migration, a phenotype dependent upon growth factors and activation of receptor tyrosine kinases (RTKs). p130(Cas) is an adaptor protein involved in several cellular signaling pathways that control cell migration, proliferation, and survival.
OBJECTIVES: We hypothesized that in experimental and human PAH p130(Cas) signaling is overactivated, thereby facilitating the intracellular transmission of signal induced by fibroblast growth factor (FGF)2, epidermal growth factor (EGF), and platelet-derived growth factor (PDGF).
MEASUREMENTS AND MAIN RESULTS: In patients with PAH, levels of p130(Cas) protein and/or activity are higher in the serum, in the walls of distal pulmonary arteries, in cultured smooth muscle cells (PA-SMCs), and in pulmonary endothelial cells (P-ECs) than in control subjects. These abnormalities in the p130(Cas) signaling were also found in the chronically hypoxic mice and monocrotaline-injected rats as models of human PAH. We obtained evidence for the convergence and amplification of the growth-stimulating effect of the EGF-, FGF2-, and PDGF-signaling pathways via the p130(Cas) signaling pathway. We found that daily treatment with the EGF-R inhibitor gefitinib, the FGF-R inhibitor dovitinib, and the PDGF-R inhibitor imatinib started 2 weeks after a subcutaneous monocrotaline injection substantially attenuated the abnormal increase in p130(Cas) and ERK1/2 activation and regressed established pulmonary hypertension.
CONCLUSIONS: Our findings demonstrate that p130(Cas) signaling plays a critical role in experimental and idiopathic PAH by modulating pulmonary vascular cell migration and proliferation and by acting as an amplifier of RTK downstream signals.

PMID: 22798315 [PubMed - indexed for MEDLINE]

zm-447439 rad001 ecdysone

Prognostic value of acquired resistance-related molecules in Japanese patients with NSCLC treated with an EGFR-TKI.

Prognostic value of acquired resistance-related molecules in Japanese patients with NSCLC treated with an EGFR-TKI.

Anticancer Res. 2012 Sep;32(9):3785-90

Authors: Uramoto H, Yamada T, Yano S, Kondo N, Hasegawa S, Tanaka F

Abstract
BACKGROUND: Most patients with lung cancer experience relapse, although epidermal growth factor receptor (EGFR) of tyrosine kinase inhibitor (TKI) has an astounding effect on tumors with EGFR-activating mutations. It is therefore critical to determine the mechanisms of resistance against agents and the prognostic value of acquired resistance-related molecules to EGFR-TKI.
MATERIALS AND METHODS: Tumor specimens were obtained from 19 matched specimens before and after treatment with gefitinib. A retrospective multi-institutional study analyzed the correlation between patients' survival and acquired resistance-related molecules in non-small cell lung cancer (NSCLC) samples, that possessed sensitive EGFR mutations (7 cases: exon 19 deletion, and 12 cases: exon 21 point mutation). The status of the epidermal growth factor receptor (EGFR) and KRAS genes were investigated by polymerase chain reaction (PCR)-based analyses. Real-time PCR assays were also used to evaluate MET gene amplification. The expression of hepatocyte growth factor (HGF) and changes in the epithelial-mesenchymal transition (EMT) status including the expression of E-cadherin and ?-catenin as epithelial markers, and those of vimentin and fibronectin as mesenchymal markers, were evaluated by immunohistochemistry.
RESULTS: Eight of the gefitinib refractory tumors exhibited a secondary threonine-to-methionine mutation at codon 790 in EGFR (T790M). All of the tumors had wild type KRAS gene expression. No MET amplification was detected in any of the samples. A strong expression of HGF was detected in eight of the specimens at post-treatment. A change in the EMT status between pre-and post-treatment was found in five cases. The 5-year survival rate of patients with and without T790M was 86.7% and 13.3%, respectively (p=0.020). The 5-year overall survival (OS) rate for patients with overexpresion and for those with weak expression of HGF was 75.0% and 22.2%, respectively (p=0.259). In addition, the 5-year OS rate for patients with unchanged and changed EMT status was 83.3% and 40.0%, respectively (p=0.123).
CONCLUSION: The current results showed that the presence of T790M is associated with favorable survival. On the other hand, the patients with weak HGF expression and EMT change tend to have a poor survival. The current patients' selection might be changed by discrimination of acquired resistance-related molecules in patients with NSCLC treated with an EGFR-TKI.

PMID: 22993320 [PubMed - indexed for MEDLINE]

ecdysone chir-258 dovitinib

Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.

Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.

Bioorg Med Chem Lett. 2012 Sep 15;22(18):5903-8

Authors: Raheem IT, Breslin MJ, Fandozzi C, Fuerst J, Hill N, Huszar S, Kandebo M, Kim SH, Ma B, McGaughey G, Renger JJ, Schreier JD, Sharma S, Smith S, Uslaner J, Yan Y, Coleman PJ, Cox CD

PMID: 22892116 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

Cardiovascular adverse effects of anti-inflammatory drugs.

Cardiovascular adverse effects of anti-inflammatory drugs.

Antiinflamm Antiallergy Agents Med Chem. 2012 Dec 31;

Authors: Roubille C, Martel-Pelletier J, Davy JM, Haraoui B, Pelletier JP

Abstract
Anti-inflammatory drugs consist of non-steroidal anti-inflammatory drugs (NSAIDs) including non-selective nsNSAIDs, aspirin, and cyclooxygenase-2 (COX-2)-selective inhibitors also referred to as coxibs, and glucocorticoids (GCs). They are worldwide prescribed drugs for many musculoskeletal conditions, such as osteoarthritis and inflammatory rheumatic diseases. Anti-inflammatory drugs can exert deleterious effects on the cardiovascular system, excluding aspirin. NSAIDs, especially coxibs, have been demonstrated to increase cardiovascular risk and have generated many concerns leading to the reassessment of their benefit/risk ratio. GCs may also induce cardiovascular events, but evidence seems to be less clear. Before prescribing these drugs, an assessment of cardiovascular risk may be judicious.In this review, anti-inflammatory drugs, coxibs, nsNSAIDs and GCs, and the risk of cardiovascular events will be discussed.

PMID: 23286294 [PubMed - as supplied by publisher]

ecdysone chir-258 dovitinib

2013年1月4日星期五

The combination of IKK? inhibitor and everolimus modulates expression of IL-10 in HTLV-1-infected T cells.

The combination of IKK? inhibitor and everolimus modulates expression of IL-10 in HTLV-1-infected T cells.

Immunology. 2012 Dec 27;

Authors: Nishioka C, Ikezoe T, Yang J, Udaka K, Yokoyama A

Abstract
Adult T-cell leukemia-lymphoma (ATLL) is an aggressive malignancy of CD4(+) /CD25(+) T lymphocytes, and characterized with severely compromised immunosystem in which the human T-cell lymphotropic virus type 1 (HTLV-1) has been recognized as the etiologic agent. This study found that an I?B kinase ? (IKK?) inhibitor Bay11-7082 inactivated mammalian target of rapamycin (mTOR), signal transducer and activator of transcription 3 (STAT3), and transcription factor nuclear factor-?B (NF-?B) in HTLV-1-infected T cells, which was significantly enhanced in the presence of an mTOR inhibitor everolimus. In addition, Bay11-7082 decreased production of immunosuppressive cytokine interleukin-10 (IL-10), which was further downregulated when Bay11-7082 was combined with evelolimus in HTLV-I-infected T and ATLL cells isolated from patients. IL-10 is known to inhibit maturation and the antigen-presenting function of dendritic cells (DCs). The culture media of HTLV-I-infected MT-1 cells which contained a great amout of IL-10 hampered TNF-?-induced maturation of DCs isolated from healthy volunteers. Notably, culture supernatant of MT-1 cells treated by the combination of Bay11-7082 and everolimus augmented maturation of DCs in association with a decrease in production of IL-10 and enhanced the allostimulatory function of DCs. Similarly, when DCs isolated from ATLL patients were treated with the combination of Bay11-7082 and everolimus, they were fully maturated and their capability to stimulate proliferation of lymphocytes was augmented. Taken together, the combination of Bay11-7082 and everolimus might exhibit immunostimulatory properties in HTLV-1-infected T and ATLL cells isolated from patients, and this combination may be potentially therapeutic to regain the compromised immunosystem in ATLL patients. � 2012 The Authors. Immunology � 2012 Blackwell Publishing Ltd.

PMID: 23278479 [PubMed - as supplied by publisher]

dna-pk coxinhibitors c-met inhibitors

Tetraploidization increases sensitivity to Aurora B kinase inhibition.

Tetraploidization increases sensitivity to Aurora B kinase inhibition.

Cell Cycle. 2012 Jul 1;11(13):2567-77

Authors: Marxer M, Foucar CE, Man WY, Chen Y, Ma HT, Poon RY

Abstract
Aurora kinases are overexpressed in many cancers and are targets for anticancer drugs. The yeast homolog of Aurora B kinase, IPL1, was found to be a ploidy-specific lethality gene. Given that polyploidization is a common feature of many cancers, we hypothesized polyploidization also sensitizes mammalian cells to inhibition of Aurora kinases. Using two models of apparent diploid vs. tetraploid cell lines (one based on the hepatocellular carcinoma cell line Hep3B and another on untransformed mouse fibroblasts), we found that tetraploid cells were more sensitive to Aurora B inhibition than their diploid counterparts. Apoptosis could be induced in tetraploid cells by two different Aurora B inhibitors. Furthermore, tetraploid cells were sensitive to Aurora B inhibition but were not affected by Aurora A inhibition. Interestingly, the underlying mechanism was due to mitotic slippage and the subsequent excessive genome reduplication. In support of this, abolition of cytokinesis with dihydrocytochalasin B resulted in similar effects on tetraploid cells as Aurora B inhibition. These results indicate that inhibition of Aurora B or cytokinesis can promote apoptosis effectively in polyploid cancer cells.

PMID: 22722494 [PubMed - in process]

chir-258 dovitinib dna-pk

订阅：博文 (Atom)