University of Oulu

<p>The University of Oulu is an international science university which creates new knowledge, well-being and innovations for the future through research and education. The University of Oulu, founded in 1958, is one of the biggest and the most multidisciplinary universities in Finland. University of Oulu sciences are: Biosciences, Humanities, Education, Economics and Business administration, Natural sciences, Medicine and Health, Engineering and Architecture, Computer Science and Electrical engineering. </p>
<p>The University of Oulu is a northern, international science university that is producing new scientific knowledge and solutions to build a more sustainable, intelligent and humane world.</p>
<p><strong>Ranking in the top three percent</strong></p>
<p>There are around 17,000 to 23,000 universities in the world depending on the method of calculation. University of Oulu is usually ranked in the top three per cent. Our strength is our publishing activity, such as citations and publications in Nature and Science. Among the fields of science, we rank well in clinical medicine, medicine, dentistry, life sciences, biology, information technology and data processing, electrical engineering, ecology and geography.</p>
<p><strong>Focus areas</strong></p>
<p>Areas, where our science-based expertise meets global challenges are:</p>
<ul>
<li><em>Sustainable materials and systems</em></li>
<li><em>Lifelong health</em></li>
<li><em>Digitalization and smart society</em></li>
<li><em>Changing climate and northern environment</em></li>
<li><em>Understanding humans in change</em></li>
</ul>
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<p>For more information, please visit the university website:</p>
<p><a href="https://www.oulu.fi/en">https://www.oulu.fi/en</a></p>


<h1 id="background">Background</h1>
<p>Human ADP-ribosyltransferases are targets for therapeutics and it was shown earlier that PARP inhibitors, targeting especially ARTD1 (PARP1), can be used to sensitize BRCA-deficient cancer cells to DNA damage. The research culminated in the approval of the first therapeutic, Lynparza/Olaparib, in 2014.</p>
<p>Recently, it has been evident that also other ADP-ribosyltransferases control multiple cellular signaling pathways by affecting protein localization, activity and stability. This has opened up a new avenue for drug discovery, as the ADP-ribosylation of specific target proteins is a key factor in e.g. cancer cell survival and cell death.</p>
<h1 id="technology-overview">Technology Overview</h1>
<p>Oulu researchers have discovered a small molecular chemical probe OUL35 for ARTD10 (PARP10) enzyme, which is potent, selective and functional in cell based assays.</p>
<p>As ARTD10 is involved in cell death, proliferation and DNA repair the found inhibitor provides a potential therapeutic strategy especially against cancer.</p>
<p>The researchers have shown that the compound sensitizes cancer cells to DNA damage though a different mechanism than the more studied ARTD1 (PARP1) inhibitors like Lynparza. The structure-activity relationship studies have shown that the scaffold can also be used to inhibit other human mono-ADP-ribosyltransferases like ARTD8/PARP14 and ARTD15/PARP7, which are also identified drug targets for treatment of hematological cancers.</p>
<h3 id="-developmental-status-"><strong>Developmental Status</strong></h3>
<p>TRL 3 (tested in cellular models)</p>
<h3 id="-references-"><strong>References</strong></h3>
<ul>
<li><strong>Discovery:</strong> Venkannagari H, Verheugd P, Koivunen J, Haikarainen T, Obaji E, Ashok Y, Narwal M, Pihlajaniemi T, Lüscher B, Lehtiö L. Small-Molecule Chemical Probe Rescues Cells from Mono-ADP-Ribosyltransferase ARTD10/PARP10-Induced Apoptosis and Sensitizes Cancer Cells to DNA Damage. (2016) <em>Cell Chem. Biol.</em> 23:1251-1260.</li>
<li><strong>Derivatives:</strong> Murthy S, Desantis, J., Verheugd, P., Maksimainen, M.M., Massari, S., Ashok, Y., Obaji, E., Nkizinkiko, Y., Lüscher, B., Tabarrini, O. &amp; Lehtiö, L. 4-(Phenoxy) and 4-(benzyloxy)benzamides as potent and selective inhibitors of mono-ADP-ribosyltransferase PARP10/ARTD10. (2018) <em>Eur. J. Med. Chem.</em> 156:93-102.</li>
<li><strong>Derivatives:</strong> Holechek J, Lease R, Thorsell AG, Karlberg T, McCadden C, Grant R, Keen A, Callahan E, Schüler H, Ferraris D. Design, synthesis and evaluation of potent and selective inhibitors of mono-(ADP-ribosyl)transferases PARP10 and PARP14. (2018) <em>Bioorg. Med. Chem. Lett.</em> 28:2050-2054.</li>
</ul>
<h1 id="benefits">Benefits</h1>
<ul>
<li>Selective for mono-ADP-ribosylating ARTD/PARP10 enzyme</li>
<li>Confirmed target engagement in cells without cytostatic/toxic effects</li>
<li>Submicromolar potency in biochemical and cell-assay</li>
<li>Sensitizes cancer cells to the clinically used chemotherapeutics</li>
<li>Potential for targeted therapeutics through inhibition of specific ARTD (PARP10) enzyme</li>
</ul>
<h1 id="applications">Applications</h1>
<ul>
<li>Treatment of cancer ‑ especially leukemia</li>
</ul>
<h1 id="opportunity">Opportunity</h1>
<ul>
<li>Potential candidate drug for leukemia (remission)</li>
<li>Increase of efficiency for chemotherapeutic drugs</li>
</ul>
