German Cancer Research Center (DKFZ)

<p><strong>Overview:</strong></p>
<p>Founded in 1964, the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) is the largest biomedical research institute in Germany and a member of the Helmholtz Association of National Research Centers.</p>
<p>In over 90 divisions and research groups, DKFZ’s more than 3,000 employees (of which more than 1,200 are scientists) are investigating the mechanisms of cancer, are identifying cancer risk factors and are trying to find strategies to prevent people from getting cancer.</p>
<p>DKFZ employees have funded over 30 spin offs. DKFZ scientist published in 2018 more than 1864 publications in ISI-referenced journals of which 373 had an impact factor &gt;10 and 124 publications were published in journals with an impact factor &gt;20. Additionally DKFZ successfully raised in 2017 over 63 Million € third party funding.</p>
<p><strong>Research:</strong></p>
<p>The departments, research groups and Clinical Cooperation Units of DKFZ are assigned to seven Research Programs including the following:</p>
<ul>
<li>Research Program Cell Biology and Tumor Biology</li>
<li>Research Program Functional and Structural Genomics</li>
<li>Research Program Cancer Risk Factors and Prevention</li>
<li>Research Program Tumor Immunology</li>
<li>Research Program Imaging and Radiooncology</li>
<li>Research Program Infections and Cancer</li>
</ul>
<p>In 2008, the Nobel Prize in Medicine awarded to Professor Harald zur Hausen, former Scientific Director of DKFZ, who discovered that human papillomaviruses (HPV) cause cervical cancer.</p>
<p>In 2014 a second DKFZ researcher, Professor Stefan W. Hell, was awarded the Nobel Prize in Chemistry for his pioneering work in the field of ultra high resolution fluorescence microscopy.</p>
<p><strong>Industry Partnerships:</strong></p>
<p>The Office of Technology Transfer of the German Cancer Research Center has been committed to making commercial use of the innovative potential of excellent cancer research since 1997. Working at the interface of research and industry, the team helps to get new cancer medications, diagnostic tests procedures, and research instruments onto the market as quickly as possible.</p>
<p>The German Cancer Research Centre engages in a multitude of national and international collaborations. About 60 percent of the Centre’s scientific publications present results with external co-authors. </p>
<p>With regards to industry partners, DKFZ also has a <a href="https://www.dkfz.de/en/dkfz-bayer-allianz/index.html">Strategic Alliance with Bayer Schering Pharma</a> and numerous contracts with other pharmaceutical companies. These collaborations draw on the strengths of partners and so expedite the process by which research findings are translated into innovative substances for cancer treatment. </p>
<p>Furthermore, there are alliances with Siemens and also with Carl Zeiss MicroImaging which led to foundation of “<a href="https://www.dkfz.de/en/aktuelles/zeiss/zeiss_applikationszentrum.html">Carl Zeiss Application Centre” in the Heidelberg Technology Park in July 2007</a></p>


<h1 id="background">Background</h1>
<p>ATM kinase, a serine threonine kinase involved in a plurality of key cellular functions, plays a major role in the DNA damage response (DDR) pathways. This kinase responds directly to double-strand breaks (DSBs) caused by common anti-cancer treatments such as ionizing radiation, topoisomerase-II inhibitors but also topoisomerase-I inhibitors. ATM kinase inhibitors can potentiate the activity of these agents and are therefore expected to be a useful combination partner in the treatment of cancer.</p>
<p>The underlying invention provides compounds that are effective in inhibiting, regulating and/or modulating ATM kinase, in particular compounds that have an increased inhibitory effect against ATM kinase. Furthermore, the compounds are effective in treatment of cancer, in particular colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphatic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer, or non-small cell lung cancer.</p>
<h1 id="technology-overview">Technology Overview</h1>
<p>ATM kinase is a serine threonine kinase which was originally identified as the product of the gene mutated in ataxia telangiectasia. ATM kinase belongs to the PIKK family of kinases having domains with homology to phosphoinositide kinases. These kinases are involved in a plurality of key cellular functions, such as cell growth, cell proliferation, migration, differentiation, survival and cell adhesion. ATM kinase responds to direct double-strand breaks caused by common anti-cancer treatments such as ionizing radiation, topoisomerase-II inhibitors but also topoisomerase-I inhibitors. ATM kinase inhibitors can potentiate the activity of these agents and are therefore expected to be useful in the treatment of cancer.</p>
<p>The compounds are based on a tricyclic imidazo[4,5-c]quinolone scaffold, which has already been applied earlier in the development of ATM kinase inhibitors. Along with a extremely efficient inhibition of the target kinase, these newly developed compounds also display additional drug-like properties e.g. good aqueous solubility, metabolic stability and a favorable selectivity profile.</p>
<h3 id="-stage-of-development-"><strong>Stage of Development</strong></h3>
<p>Biological evaluation of the compounds:</p>
<ul>
<li>Calculation of the IC50 value with an enzymatic ATM assay</li>
<li>Calculation of the IC50 value in two different cancer cell lines</li>
</ul>
<h3 id="-further-detail-"><strong>Further Detail</strong></h3>
<p>Teodor Dimitrov, Cetin Anli, Athina Anastasia Moschopoulou, Thales Kronenberger, Mark Kudolo, Christian Geibel, Martin Peter Schwalm, Stefan Knapp, Lars Zender, Michael Forster, Stefan Laufer: <strong>Development of novel urea-based ATM kinase inhibitors with subnanomolar cellular potency and high kinome selectivity.</strong> European Journal of Medicinal Chemistry, Volume 114234, 23 May, 2022. <a href="https://doi.org/10.1016/j.ejmech.2022.114234" title="Persistent link using digital object identifier">https://doi.org/10.1016/j.ejmech.2022.114234</a></p>
<h1 id="benefits">Benefits</h1>
<ul>
<li>Compounds for effective inhibition, regulation and/or modulation of ATM kinase</li>
<li>Compounds are effective in treatment of cancer as confirmed in two pancreatic cancer cell lines</li>
<li>Compounds have better efficacy based on <em>in vitro</em> data compared to already available ATM kinase inhibitors. Biochemical IC50 in single digit nanomolar range and cellular IC50 in nanomolar to micromolar range</li>
</ul>
<h1 id="applications">Applications</h1>
<ul>
<li>Targeted therapy of ATM mediated diseases, especially cancer.</li>
<li>Adjuvant therapy to all radiation treated cancers</li>
<li>Adjuvant therapy to treatments, which intentionally induce double-strand breaks</li>
</ul>
<h1 id="opportunity">Opportunity</h1>
<p>Seeking licensing</p>
