The interactions of extracellular ligands with single membrane spanning receptors, such as kinases, typically serve to agonise or antagonise the intracellular activation of signalling pathways. Within the cell, E3 ligases can act to alter the localisation and activity of proteins involved in signalling systems. Structural and functional characterisation of two closely related single membrane spanning molecules, RNF43 and ZNRF3, has recently revealed the receptor-like functionalities of a ligand-binding ectodomain combined with the intracellular architecture and activity of an E3 ligase. This direct link provides a hereto novel mechanism for extracellular control of ubiquitin ligase activity that is used for the modulation of Wnt signalling, a pathway of major importance in embryogenesis, stem cell biology and cancer. In this review we discuss recent findings for the structure and interactions of the extracellular region of RNF43/ZNRF3 and draw parallels with the properties and function of signalling receptor ectodomains.
Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

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On Apr 21, 2016 Immune Therapeutics Inc. (OTCQB: IMUN) reported that they have signed a binding Letter of Intent to acquire Chinese Chimeric Super Antigen Receptor T cell (CAR-T) cocktail therapy, Immuno-Oncology patents (pending), manufacturing technology, and clinical data of the aforementioned therapies from Super-T Cell Cancer Company ("STCC") a newly formed corporation (Press release, Immune Therapeutics, APR 21, 2016, View Source [SID:1234514893]).

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"This CAR-T cell technology licensing further accelerates IMUN’s growth in the Immuno-Oncology field as we evaluate paths to commercialization both in China and other Emerging Markets," commented Christopher Pearce, Chief Operating Officer.
CAR-T cell therapy involves engineering cancer patients’ own immune cells to recognize and attack cancer tumors. CAR-T therapy has great potential to improve patient-specific cancer therapy in a profound way. N umerous studies have implicated regulatory T cells as key mediators in the creation of an immunosuppressed microenvironment that enables tumors to escape attack by the host immune system. The Super CAR-T Cocktail therapy has shown promise in early human clinical trials for the treatment of blood cancer, renal, cervical and hepatic cancer.

"We are very impressed by the quality of the work done by Professor Shan and his team, and are excited by the safe and efficacious profile of this novel CAR-T cocktail therapy for cancerous diseases. This is the beginning of a long-term strategic partnership between IMUN and STCC. Together, we will expeditiously continue our quest in developing more affordable, safer, and more effective cancer immunotherapy programs," said Noreen Griffin, Chief Executive Officer of Immune Therapeutics, Inc.
The need in China for new affordable therapies is critical. It is predicted that there will be about 4,292,000 newly diagnosed invasive cancer cases in 2016, corresponding to almost 12,000 new cancer diagnoses on average each day. IMUN believes that once approved it could capture 5% of the market in the first year.

Inhibition of phosphoinositide 3-kinase (PI3K) signaling is an appealing approach to treat brain tumors, especially glioblastoma multiforme (GBM). We previously disclosed our successful approach to prospectively design potent and blood-brain barrier (BBB) penetrating PI3K inhibitors. The previously disclosed molecules were ultimately deemed not suitable for clinical development due to projected poor metabolic stability in humans. We, therefore, extended our studies to identify a BBB penetrating inhibitor of PI3K that was also projected to be metabolically stable in human. These efforts required identification of a distinct scaffold for PI3K inhibitors relative to our previous efforts and ultimately resulted in the identification of GDC-0084 (16). The discovery and preclinical characterization of this molecule are described within.

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Sonidegib selectively inhibits smoothened protein, suppresses the growth of Hedgehog pathway-dependent tumors, and has recently been approved in the indication of locally advanced basal cell carcinoma. A comprehensive exposure-response analysis was conducted to further characterize the relationship of sonidegib exposure to efficacy and safety. Minimum observed plasma concentration at pre-dose (Cmin), peak concentration (Cmax), and area under the curve were used as exposure endpoints. Exposure-efficacy analyses included data from 190 patients who received sonidegib 200 mg or 800 mg once daily in the primary efficacy study. Objective response rate (ORR) (complete response [CR] or partial response [PR]), progression-free survival (PFS), and time to tumor response (TTR) were assessed by logistic regression, Cox regression and Kaplan-Meier analyses. Exposure-safety (creatine phosphokinase [CK] elevation) analyses included data from 336 patients pooled from four clinical trials and included doses across ranges of 100-3000 mg once daily and 250-750 mg twice daily. Similar plasma exposure was observed between responders and non-responders. The logistic regression model of Week 5 Cmin vs. ORR indicated no relationship between sonidegib exposure resulting from 200 mg or 800 mg doses and the probability of CR or PR. A similar conclusion of no exposure-efficacy relationship was drawn from the PFS and TTR analyses. Increased exposure was associated with a greater risk of Grade 3 or 4 CK elevation, with lower risk in females than in males when using Cmin in the model. These analyses support the sonidegib dose recommendation for registration and are consistent with clinical observations. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.

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The prenyl-binding protein PDEδ is crucial for the plasma membrane localization of prenylated Ras. Recently, we have reported that the small-molecule Deltarasin binds to the prenyl-binding pocket of PDEδ, and impairs Ras enrichment at the plasma membrane, thereby affecting the proliferation of KRas-dependent human pancreatic ductal adenocarcinoma cell lines. Here, using structure-based compound design, we have now identified pyrazolopyridazinones as a novel, unrelated chemotype that binds to the prenyl-binding pocket of PDEδ with high affinity, thereby displacing prenylated Ras proteins in cells. Our results show that the new PDEδ inhibitor, named Deltazinone 1, is highly selective, exhibits less unspecific cytotoxicity than the previously reported Deltarasin and demonstrates a high correlation with the phenotypic effect of PDEδ knockdown in a set of human pancreatic cancer cell lines.

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