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Investigation on the ZBG-functionality of phenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase inhibitors.

A series of alternative Zn-binding groups were explored in the design of phenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors. Most of the synthesized compounds were less effective than the parent hydroxamic acid. However, the profile of activity shown by the analog bearing a hydroxyurea head group, makes this derivative promising for further investigation.
Copyright © 2015 Elsevier Ltd. All rights reserved.

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Synthesis and Antiproliferative and Metabolic Evaluations of Novel Securinine Derivatives.

New securinine analogues have been prepared by semisynthesis. Two series were developed using either Suzuki or Sonogashira cross coupling reactions. The in vitro cytotoxicity of the compounds was assayed against HCT-116 colon cancer cells. The most potent derivatives showed promising growth inhibition on four tumoral cell lines giving a valuable insight on the structure-activity relationship (SAR) of securinine. Moreover, high antiproliferative effect against A-375 (melanoma) was observed with IC50 up to 60 nM.

Onconova Announces Publication Describing Unique RAS-targeted Mechanism of Action for Rigosertib in the Journal Cell

On April 21, 2016 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, reported that researchers from the Icahn School of Medicine at Mount Sinai, led by Professor E. Premkumar Reddy, scientific founder of Onconova, have published a study describing the novel RAS-targeted mechanism of action for rigosertib in the journal Cell (Press release, Onconova, APR 21, 2016, View Source [SID:1234511258]). The paper, titled "A small molecule RAS-mimetic disrupts RAS association with effector proteins to block signaling," can be accessed in the current online edition of Cell.

RAS represents one of the most sought-after targets in cancer. Thus far the development of drugs to block RAS has been difficult, leading many to label RAS the undruggable oncogene.

"This discovery is the culmination of my laboratory’s work with RAS genes over the last three decades," said Dr. E. Premkumar Reddy, lead author of the paper and Professor of Oncological Sciences at the Icahn School of Medicine at Mount Sinai. "RAS genes have been a challenging target for molecular oncologists and drug developers. However, the allosteric mechanism by which rigosertib blocks activation of signaling proteins downstream of RAS may represent a new paradigm for attacking this oncogene."

The research published in Cell and carried out by a multidisciplinary team from Mount Sinai, The Scripps Cancer Research Institute, Albert Einstein College of Medicine, and the New York Structural Biology Center, demonstrated that rigosertib blocks RAS signaling by directly binding to various RAS effector proteins, including RAF and PI3-kinase. These mechanistic findings support the development of rigosertib in malignancies with over-activate RAS signaling, such as higher-risk myelodysplastic syndromes (HR-MDS). Onconova is actively enrolling patients in the global INSPIRE trial, a randomized Phase 3 study to assess the efficacy and safety of single-agent intravenous rigosertib in HR-MDS.

About Rigosertib

Rigosertib is a small molecule inhibitor of cellular signaling and acts as a Ras mimetic. These effects of rigosertib appear to be mediated by direct binding of the compound to the Ras-binding domain (RBD) found in many Ras effector proteins, including the Raf kinases and PI3K. The initial therapeutic focus for rigosertib is myelodysplastic syndromes (MDS), a group of bone marrow disorders characterized by ineffective formation of blood cells that often converts into acute myeloid leukemia (AML). Clinical trials for rigosertib are being conducted at leading institutions in the United States, Europe, and the Asia-Pacific region. Rigosertib is protected by issued patents (earliest expiry in 2026) and has been awarded Orphan Designation for MDS in the United States, Europe and Japan.

About RAS

Point mutations in RAS genes (HRAS, KRAS and NRAS) are frequently observed in many of the most common and lethal tumors, including cancers of the pancreas, lung, colon, skin, bladder and bone marrow. RAS genes encode important intracellular proteins that when mutated activate pathways involved in cancer cell proliferation, survival and metastasis. Although molecular oncologists have made significant headway in understanding RAS mutations and their impact on cellular signaling, less progress has been made towards developing RAS-targeted drugs. Thus, there is an urgent need for new therapeutic modalities that address this important oncogene.

Opportunities and challenges in leveraging electronic health record data in oncology.

The widespread adoption of electronic health records (EHRs) and the growing wealth of digitized information sources about patients is ushering in an era of ‘Big Data’ that may revolutionize clinical research in oncology. Research will likely be more efficient and potentially more accurate than the current gold standard of manual chart review studies. However, EHRs as they exist today have significant limitations: important data elements are missing or are only captured in free text or PDF documents. Using two case studies, we illustrate the challenges of leveraging the data that are routinely collected by the healthcare system in EHRs (e.g., real-world data), specific challenges encountered in the cancer domain and opportunities that can be achieved when these are overcome.

OncoMed Announces Clinical Data to be Presented at the 2016 ASCO Annual Meeting

On April 21, 2016 OncoMed Pharmaceuticals Inc. (NASDAQ:OMED) reported it will present data from several clinical programs at the upcoming American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2016 Annual Meeting being held June 3-7, 2016 in Chicago, IL (Press release, OncoMed, APR 21, 2016, View Source [SID:1234511238]).

Presentations include the first clinical data of OncoMed’s Wnt pathway inhibitors (vantictumab and ipafricept) in combination therapy. The Phase 1b vantictumab (anti-Fzd7, OMP-18R5) clinical trial is in combination with paclitaxel in breast cancer and the Phase 1b ipafricept (FZD8-Fc, OMP-54F28) clinical trial is in combination therapy with carboplatin and paclitaxel in ovarian cancer.

In addition, updated survival data from OncoMed’s Phase 1b clinical trials of demcizumab (OMP-21M18, anti-DLL4) in non-small cell lung cancer (NSCLC) and of tarextumab (anti-Notch2/3, OMP-59R5) in small cell lung cancer will be presented.

A complete list of OncoMed’s accepted abstracts is provided below.

Poster Discussions

Saturday, June 4, 3:00pm – 4:15pm CT at E354b

1. Abstract #9023: A Phase 1b Study of the Anti-Cancer Stem Cell Agent Demcizumab (DEM), Pemetrexed (PEM) & Carboplatin (CARBO) in Patients (pts) with 1st Line Non-Squamous NSCLC

Presenter: Mark James McKeage, MBChB, MMedSc, PhD, FRACP, Auckland City Hospital and University of Auckland
Session: Lung Cancer – Non-Small Cell Metastatic
Poster Display: Hall A; Poster Board#346; 8:00 am – 11:30am CT

Sunday, June 5, 11:30am – 12:45pm CT at Arie Crown Theater

2. Abstract #2515: Phase 1b of WNT inhibitor Ipafricept (IPA, decoy receptor for WNT ligands) with Carboplatin (C) and Paclitaxel (P) in Recurrent Platinum-Sensitive Ovarian Cancer (OC)

Presenter: Roisin E. O’Cearbhaill, M.D., Memorial Sloan Kettering Cancer Center
Session: Developmental Therapeutics – Clinical Pharmacology and Experimental Therapeutics
Poster Display: Hall A; Poster Board #215; 8:00am – 11:30am CT

3. Abstract #2516: Phase 1b Study of WNT Inhibitor Vantictumab (VAN, human monoclonal antibody) with Paclitaxel (P) in Patients (pts) with 1st- to 3rd-Line Metastatic HER2-Negative Breast Cancer (BC)

Presenter: Monica Mita, MD, Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute
Session: Developmental Therapeutics – Clinical Pharmacology and Experimental Therapeutics
Poster Display: Hall A; Poster Board #216; 8:00am – 11:30am CT

Poster

Saturday, June 4, 8:00am — 11:00am CT

Abstract #8564: Updated results of Phase 1b study of tarextumab (TRXT, anti-Notch2/3) in combination with etoposide and platinum (EP) in patients (pts) with untreated extensive-stage small-cell lung cancer (ED-SCLC)
Lead author: Anne Chiang, M.D., Ph.D., of the Yale School of Medicine
Session: Lung Cancer — Non-small Cell Local-regional/Small Cell/Other Thoracic Cancers
Location: Hall A; Poster Board#192