Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity(R), the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: (Z)-4-Hydroxytamoxifen, [18F]-FPS; Adalimumab, alefacept, alemtuzumab, alfimeprase, aprepitant, aripiprazole, atomoxetine hydrochloride; Belatacept, bortezomib; C340, caspofungin acetate, clazosentan sodium, Cypher; Darbepoetin alfa, DB-289, decitabine, dronedarone hydrochloride, duloxetine hydrochloride; Eletriptan, entecavir, ertapenem sodium, escitalopram oxalate, eszopiclone, etoricoxib; Gaboxadol, gadofosveset sodium, galiximab, gemifloxacin mesilate, glutamine; Human insulin; I-131 ch-TNT-1/B, indiplon, inhaled insulin, isatoribine; L-Arginine hydrochloride, liposomal doxorubicin, lopinavir/ritonavir, lumiracoxib; Magnesium sulfate; Natalizumab; Olmesartan medoxomil, omapatrilat, OncoVEX (GM-CSF); rDNA insulin, rupatadine fumarate; Sorafenib; Tadalafil, teduglutide, temsirolimus, tenofovir disoproxil fumarate, tiotropium bromide; Valdecoxib, vardenafil hydrochloride hydrate.
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PMID:Gateways to clinical trials. 1635 53

Immunosuppressive drugs have been traditionally developed to prevent acute rejection and to improve short-term kidney transplant outcomes. There is still a medical need to improve outcomes among subgroups of patients at higher risk for graft loss and to reduce cardiovascular, infectious and malignancy-associated morbidity and mortality, and improve long-term adherence. Several new immunosuppressive agents and formulations are undergoing clinical investigation and are discussed in this review.A modified release tacrolimus formulation (MR4) for once-daily administration is undergoing phase III trials. It has been developed to be administered de novo or for maintenance using the same therapeutic target tacrolimus trough concentrations as for the original formulation. Belatacept (LEA29Y), a second generation cytotoxic-T-lymphocyte-associated antigen immunoglobulin (CTLA4-Ig), blocks the interaction between CD80/86 and CD28 costimulatory pathways. In phase II trials, belatacept was as effective as ciclosporin (cyclosporine) when administered in combination with basiliximab, mycophenolate mofetil (MMF) and corticosteroids. Currently, belatacept is undergoing phase III trials including one study in recipients of organs from expanded criteria donors. Inhibitors of the Janus protein tyrosine kinase (JAK)-3 show some selectivity for cells of the lymphoid lineage and have been shown to be effective in late preclinical transplant models. The most frequent adverse effects have been related to nonspecific binding to JAK2 kinases. CP-690550, a JAK3 inhibitor is currently in phase II clinical trials.FK778, is a synthetic malononitrilamide that targets the critical enzyme of the de novo pyrimidine synthesis, dihydroorotic acid dehydrogenase, and receptor-associated tyrosine kinases has completed phase II trials. FK778 also shows antiviral activities that have been tested in patients with polyomavirus nephropathy. Fingolimod (FTY720), a synthetic sphingosine phosphate receptor modulator that reduces the recirculation of lymphocytes to blood and peripheral tissues including inflammatory lesions and graft sites is undergoing phase III trials. Although the efficacy of fingolimod is similar to MMF in patients receiving full doses of ciclosporin, safety issues such as a negative chronotropic effect, macular oedema, pulmonary adverse reactions and graft function resulted in premature discontinuation of the development programme for kidney transplantation. Because there was no clear clinical benefit over treatment options, the clinical development programme of FK778 was discontinued.Finally, a new evolving strategy with powerful induction-induced prolonged T-cell depletion followed by low-dose immunosuppressive monotherapy is showing promising results.
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PMID:Immunotherapy for De Novo renal transplantation: what's in the pipeline? 1697 33

The last several decades have seen a substantial decrease in the prevalence of acute allograft rejection in kidney transplant recipients, while equivalent improvements in long-term graft function have not been realized. As a result, the primary focus of new immunosuppressive drug development has expanded to include ease of use, improved side effect profiles, and reduced nephrotoxicity in addition to the more traditional goal of improved short-term outcomes. A number of novel drugs are currently under investigation in Phase I, II, or III clinical trials primarily to replace the nephrotoxic but highly effective calcineurin inhibitors. ISA247 (voclosporine) is a cyclosporine (CsA) analog with reduced nephrotoxicity in Phase III study. AEB071 (sotrastaurin), a protein kinase C inhibitor, and CP-690550, a JAK3 inhibitor, are small molecules in Phase II studies. Everolimus is derived from the mTOR inhibitor sirolimus and is in Phase III study. Belatacept is a humanized antibody that inhibits T-cell costimulation and has shown encouraging results in multiple Phase II and III trials. Alefacept and Efaluzimab are humanized antibodies that inhibit T-cell adhesion and are in Phase I and II clinical trials. This article reviews the mechanisms of action as well as published and preliminary results of the Phase I-III clinical trials involving these novel immunosuppressive agents.
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PMID:Novel immunosuppressive agents in kidney transplantation. 2042 Jul 93

Calcineurin inhibitors (CNIs) have failed to improve long-term renal allograft survival. Their association with cardiovascular morbidity in addition to their suboptimal inhibition of a chronic alloimmune response has shifted investigative efforts toward CNI-free regimens. Sotrastaurin, a small molecule targeting protein kinase C isoforms, failed to provide adequate immunosuppression, whereas the Janus kinase 3 inhibitor tofacitinib's success in the treatment of rheumatoid arthritis led to biopharma's abandonment of it as a transplant agent. Like tofacitinib, tocilizumab, a biologic targeting the IL-6 pathway, has been approved for use in rheumatoid arthritis and interest in transplantation has been confined to several investigator-initiated trials. Belatacept, a second-generation, higher avidity variant of CTLA4Ig (abatacept), was approved by the Food and Drug Administration for prophylaxis of transplant rejection in 2011. Long-term follow-up of recipients on belatacept has demonstrated superior glomerular filtration rates as compared with CNIs, albeit with an increased risk of early and histologically severe rejection. Focus on optimizing belatacept-inclusive regimens has led to studies using lymphocyte depletion as induction and maintenance therapy with target of rapamycin inhibitors. ASKP1240, the most advanced of the anti-CD40 antibodies targeting the CD40/CD154 costimulatory pathway has just completed a phase II trial with a CNI-free arm. Animal models suggest that its highest efficacy may be in combination with belatacept. Finally, nonagonistic CD28 antibodies, which would allow CTLA4 and PD-LI binding of CD80/CD86 and activation of inhibitory pathways, have re-emerged with 2 anti-CD28 candidates in preclinical development. A reliable nontoxic CNI-free regimen may ultimately require the combination of biologic agents that provide efficacy as well as safety.
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PMID:An Update on Calcineurin Inhibitor-Free Regimens: The Need Persists, but the Landscape has Changed. 2700 97