Uncategorized – Page 16022 – 1stOncology™: Cancer Intelligence Service

Small molecule inhibitor of apoptosis proteins antagonists: a patent review.

The family of inhibitor of apoptosis proteins (IAPs) plays a key role in the suppression of proapoptotic signaling; hence, a small molecule that disrupts the binding of IAPs with their functional partner should restore apoptotic response to proapoptotic stimuli in cells. The continued publication of new patent applications of IAP antagonists over the past 4 years is a testament to the continued interest surrounding the IAP family of proteins.
This review summarizes the IAP antagonist patent literature from 2010 to 2014. Monovalent and bivalent Smac mimetics will be covered as well as two new developments in the field: IAP antagonists coupled to or merged with other targeted agents and new BIR2 selective IAP antagonists.
In addition to the well-explored scaffolds for monovalent and bivalent Smac-mimetics, some companies have taken more drastic approaches to explore new chemical space – for example, fragment-based approaches and macrocyclic inhibitors. Furthermore, other companies have designed compounds with alternative biological profiles – tethering to known kinase binding structures, trying to target to the mitochondria or introducing selective binding to the BIR2 domain. An overview of the status for the four small molecule IAP antagonists being evaluated in active human clinical trials is also provided.

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Metabolite profiling of (14)C-omacetaxine mepesuccinate in plasma and excreta of cancer patients.

Omacetaxine mepesuccinate (hereafter referred to as omacetaxine) is a protein translation inhibitor approved by the US Food and Drug Administration for adult patients with chronic myeloid leukemia with resistance and/or intolerance to two or more tyrosine kinase inhibitors. The objective was to investigate the metabolite profile of omacetaxine in plasma, urine and faeces samples collected up to 72 h after a single 1.25-mg/m(2) subcutaneous dose of (14)C-omacetaxine in cancer patients. High-performance liquid chromatography mass spectrometry (MS) (high resolution) in combination with off-line radioactivity detection was used for metabolite identification. In total, six metabolites of omacetaxine were detected. The reactions represented were mepesuccinate ester hydrolysis, methyl ester hydrolysis, pyrocatechol conversion from the 1,3-dioxole ring. Unchanged omacetaxine was the most prominent omacetaxine-related compound in plasma. In urine, unchanged omacetaxine was also dominant, together with 4′-DMHHT. In feces very little unchanged omacetaxine was found and the pyrocatechol metabolite of omacetaxine, M534 and 4′-desmethyl homoharringtonine (4′-DMHHT) was the most abundant metabolites. Omacetaxine was extensively metabolized, with subsequent renal and hepatic elimination of the metabolites. The low levels of the metabolites found in plasma indicate that the metabolites are unlikely to contribute materially to the efficacy and/or toxicity of omacetaxine.

Toll-like receptors in hepatocellular carcinoma: potential novel targets for pharmacological intervention.

Toll-like receptors (TLRs) are expressed by a wide variety of cell types including immune cells. They play a crucial role in the inflammatory and host defense response against microorganisms, and triggering TLRs can mediate the activation of innate immunity. Furthermore, research suggests that various TLRs may function differently on different tumor cells. The change in TLR activity may elicit an anti-tumor activity in hepatocellular carcinoma (HCC) cells and may serve as a novel therapeutic target for HCC therapy. Areas covered: This review discusses the role of the TLR family in HCC and the underlying signaling pathway of TLRs as a form of pattern recognition receptor in mediating inflammation and HCC immunity responses. Agonists and antagonists of TLRs, which render TLRs as potential therapeutic targets, activate downstream molecules, subsequently causing HCC cell survival. The proliferation or protection against the development of HCC is also described. Expert opinion: A series of studies have highlighted a crucial role of TLRs in HCC and consider TLR signaling pathways as potential therapeutic targets for HCC. However, the conclusions of these studies are in part paradoxical and controversial. Thus, it is necessary to extend further research to help determine the signaling pathways involved.

Assessment of ALK gene fusions in lung cancer using the differential expression and exon integrity methods.

Anaplastic lymphoma kinase (ALK) gene fusion is a driving mutation underlying the development of non-small cell lung cancer (NSCLC). Accurate detection of ALK fusion is critical for the use of ALK inhibitors in the treatment of NSCLC. Commonly utilized methods for ALK detection include fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). However, these methods are time-consuming and costly. In the present study, a method for assessing ALK gene fusion based on the differential expression levels of the ALK kinase and non-kinase domains was developed and evaluated, with the aim of providing a convenient and reliable method for the detection of ALK fusion. In addition, another method was established to determine the integrity of exons 19-20 and 20-21 of ALK, two genomic loci that are typically broken in ALK fusions. These novel methods were applied to detect ALK fusion in 100 NSCLC patients, and were compared with IHC and FISH methods. The novel methods developed in the present study successfully detected ALK fusions in 10 samples. The concordances between the novel methods and IHC and FISH were 100%. Furthermore, the differential expression method was able to detect ALK fusions in cell-free urine samples, which was advantageous over FISH and IHC. The novel methods developed in the present study are cost-effective and easy to perform, and may provide simple and convenient techniques for the clinical assessment of ALK fusions, facilitating the use of targeted therapy for NSCLC.

Commencement of First-in-Human Clinical Trial for New Molecular Targeting Drug, Co-Developed with The University of Tokyo and National Cancer Center, to Treat Malignant Lymphoma (Including Adult T-cell Leukemia-Lymphoma)

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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Category: Uncategorized

Small molecule inhibitor of apoptosis proteins antagonists: a patent review.

Metabolite profiling of (14)C-omacetaxine mepesuccinate in plasma and excreta of cancer patients.

Toll-like receptors in hepatocellular carcinoma: potential novel targets for pharmacological intervention.

Assessment of ALK gene fusions in lung cancer using the differential expression and exon integrity methods.

Commencement of First-in-Human Clinical Trial for New Molecular Targeting Drug, Co-Developed with The University of Tokyo and National Cancer Center, to Treat Malignant Lymphoma (Including Adult T-cell Leukemia-Lymphoma)