On March 22, 2016 The National Cancer Center, The University of Tokyo, and Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported a collaboration to develop a histone methylation enzyme EZH1/2 dual inhibitor (DS-3201), as a new molecular targeting agent for hematologic malignancy, and the commencement of Phase 1*1 clinical trial in patients with malignant lymphoma and adult T-cell leukemia-lymphoma (ATL) (Press release, Daiichi Sankyo, MAR 22, 2016, View Source [SID:1234511231]).

One contributing factor to the poor prognosis for malignant lymphoma is the existence of Cancer Stem Cells*2 capable of regenerating cancer cells and thought to persist after treatment, making the eradication of Cancer Stem Cells essential to the cure of hematologic malignancy. National Cancer Center Research Institute, Division of Hematological Malignancy research group led by Issay Kitabayashi discovered that EZH1/2 are essential enzymes in the maintenance of Cancer Stem Cells, and produced research results suggesting that inhibiting both enzymes may eradicate Cancer Stem Cells to overcome drug-resistance and suppress recurrence. To date, several preclinical studies suggest that this may be an effective treatment for acute myeloid leukemia (AML) and malignant lymphoma.

Searching for an effective ATL treatment, a research group chiefly led by Professor Toshiki Watanabe and Project Research Assistant, Makoto Yamagishi, of The University of Tokyo, Graduate School of Frontier Sciences, discovered an abnormal accumulation of epigenetic changes*3 due to inappropriate activation of EZH1/2 in ATL cells. Also, as ATL cells are more strongly dependent on epigenetic changes caused by EZH1/2 compared to normal cells, the research developed a new compound that simultaneously inhibits the function of both EZH1 and EZH2. This dual inhibitor reversed inappropriate methylation of histones in ATL cells and also selectively eliminated ATL cells and HTLV-1-infected immortalized cells in the peripheral blood.

Malignant lymphoma
Malignant lymphoma is the most prevalent hematologic malignancy. Malignant lymphoma is classified into Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL). Recent advances in the management have led to the improvement in therapeutic outcomes of patients with malignant lymphoma, especially Hodgkin lymphoma and B-cell non-Hodgkin lymphoma. However, relapsed or refractory patients with both diseases and T-cell lymphoma patients are still of unfavorable prognosis. Among various subtypes of T-cell lymphoma, ATL is the disease caused by human T-cell leukemia virus type I (HTLV-1) with the poorest prognosis. About 1,000 patients suffer from ATL every year in Japan, where approximately 1.2 million individuals are infected by HTLV-1. The number of HTLV-1-infected individuals (carriers) is estimated to be about 10 to 20 million in the world. About 5 percent of carriers develop ATL during their lifetimes. However, no onset prevention methods or effective treatments of ATL have been established. The prognosis of ATL is very poor mainly because of the high frequency of drug resistance. As the only HTLV-1 endemic country among developed nations, the world expects Japan to lead global efforts to develop new treatments towards onset prevention and effective treatments of ATL.

Clinical trial
This Phase I is the multicenter, study conducted by the National Cancer Center Hospital (Chuo-ku, Tokyo), and other facilities in Japan.

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We report the discovery and optimisation of a series of 8-(2,3-dihydro-1,4-benzoxazin-4-ylmethyl)-2-morpholino-4-oxo-chromene-6-carboxamides, leading to compound 16 as a potent and selective PI3Kβ/δ inhibitor: PI3Kβ cell IC50 0.012μM (in PTEN null MDA-MB-468 cell) and PI3Kδ cell IC50 0.047μM (in Jeko-1 B-cell), with good pharmacokinetics and physical properties. In vivo, 16 showed profound pharmacodynamic modulation of AKT phosphorylation in a mouse PTEN-deficient PC3 prostate tumour xenograft after a single oral dose and gave excellent tumour growth inhibition in the same model after chronic oral dosing. Compound 16 was selected as a preclinical candidate for the treatment of PTEN-deficient tumours.
Copyright © 2016 Elsevier Ltd. All rights reserved.

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Mesenchymal stem/stromal cells (MSCs) have been extensively investigated for their regenerative, immune-modulatory, and wound healing properties. While the laboratory studies have suggested that MSC’s have a unique potential for modulating the etiopathology of multiple diseases, the results from clinical trials have not been encouraging or reproducible. One of the explanations for such variability is explained by the "art" of isolating and propagating MSCs. Therefore, establishing more than minimal criteria to define MSC would help understand best protocols to isolate, propagate and deliver MSCs. Developing a calibration standard, a database and a set of functional tests would be a better quality metric for MSCs. In this review, we discuss the importance of selecting a standard, issues associated with coming up with such a standard and how these issues can be mitigated.
Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

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MTH1 (NUDT1) is an oncologic target involved in the prevention of DNA damage. We investigate the way MTH1 recognises its substrates and present substrate-bound structures of MTH1 for 8-oxo-dGTP and 8-oxo-rATP as examples of novel strong and weak binding substrate motifs. Investigation of a small set of purine-like fragments using 2D NMR resulted in identification of a fragment with weak potency. The protein-ligand X-Ray structure of this fragment provides insight into the role of water molecules in substrate selectivity. Wider fragment screening by NMR resulted in three new protein structures exhibiting alternative binding configurations to the key Asp-Asp recognition element of the protein. These inhibitor binding modes demonstrate that MTH1 employs an intricate yet promiscuous mechanism of substrate anchoring through its Asp-Asp pharmacophore. The structures suggest that water-mediated interactions convey selectivity towards oxidized substrates over their non-oxidised counterparts, in particular by stabilization of a water molecule in a hydrophobic environment through hydrogen bonding. These findings may be useful in the design of inhibitors of MTH1.

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The goal of these studies was to extensively characterize the first recombinant FIX therapeutic corresponding to the threonine-148 (Thr-148) polymorph, IXINITY (trenonacog alfa [coagulation factor IX (recombinant)]). Gel electrophoresis, circular dichroism, and gel filtration were used to determine purity and confirm structure. Chromatographic and mass spectrometry techniques were used to identify and quantify posttranslational modifications. Activity was assessed as the ability to activate factor X (FX) both with and without factor VIIIa (FVIIIa) and in a standard clotting assay. All results were consistent across multiple lots. Trenonacog alfa migrated as a single band on Coomassie-stained gels; activity assays were normal and showed <0.002 IU of activated factor IX (FIXa) per IU of FIX. The molecule has >97%  γ-carboxylation and underwent the appropriate structural change upon binding calcium ions. Trenonacog alfa was activated normally with factor XIa (FXIa); once activated it bound to FVIIIa and FXa. When activated to FIXa, it was inhibited efficiently by antithrombin. Glycosylation patterns were similar to plasma-derived FIX with sialic acid content consistent with the literature reports of good pharmacokinetic performance. These studies have shown that trenonacog alfa is a highly pure product with a primary sequence and posttranslational modifications consistent with the common Thr-148 polymorphism of plasma-derived FIX.

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