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Silmitasertib
open-in-new
<h2 id="mechanism-of-action">Mechanism of action</h2> <p>Silmitasertib interacts <a href="/facts/Competitive_inhibition/AQ3PLzBe">competitively</a> with the <a href="/facts/Adenosine_triphosphate/nB9bwgcU">ATP</a>-binding site of <a href="/facts/Casein_kinase_2,_alpha_1/kfnSXaUM">CK2 subunit alpha</a>. This leads to inhibition of several downstream <a href="/facts/Cell_signaling/6oYAVP9I">signaling pathways</a>, including <a href="/facts/Akt/PKB_signaling_pathway/S22sQFUq">PI3K/Akt</a>.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a><a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> </p> <h2 id="covid-19-infections">COVID-19 infections</h2> <p>In SARS-CoV-2 (COVID-19) infected <a href="/facts/Caco-2/UC6xIrvR">Caco-2</a> cells, the phosphorylase activity of <a href="/facts/Casein_kinase_2/45eAthEg">casein kinase 2</a> (CK2) is increased resulting in phosphorylation of several cytoskeletal proteins. These infected cells also display CK2-containing <a href="/facts/Filopodia/wA6xunR3">filopodia</a> protrusions associated with budding viral particles. Hence the protrusions may assist the virus in infecting adjacent cells. In these same cells, the CK2 inhibitor silmitasertib displayed potent antiviral activity.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> Senhwa Biosciences and the US <a href="/facts/National_Institutes_of_Health/G3Eytfcc">National Institutes of Health</a> have announced that they will evaluate the efficacy of silmitasertib in treating COVID-19 infections.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> </p> <h2 id="history">History</h2> <p>CX-4945 was originated by now-defunct Cylene Pharmaceuticals of San Diego, California, as the culmination of a lengthy process of <a href="/facts/Drug_design/XAU0Ke3d">rational, structure-based</a> <a href="/facts/Molecular_modification/SMUdXQm8">molecular modification</a> of a <a href="/facts/Lead_compound/5wFoEqmS">lead compound</a> known to have <a href="/facts/PARP_inhibitor/e0Nfu55P">PARP inhibitor</a> activity.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> Among a large series of compounds built around a benzo[<i>c</i>]-[2,6]<a href="/facts/Naphthyridine/pUJJDq3E">naphthyridine</a>-8-carboxylic acid scaffold, CX-4945 was chosen for its high potency and selectivity as an inhibitor of CK2.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> </p><p>Preclinical <a href="/facts/Pharmacokinetics/x4CUUnle">pharmacokinetics</a> studies conducted in mice, rats, and dogs confirmed that CX-4945 had satisfactory <a href="/facts/Bioavailability/9l6na9MV">bioavailability</a> when given by mouth and did not block <a href="/facts/Cytochrome_P450/alxusFD0">cytochrome P450</a>, while experiments in mice confirmed its inhibition of solid-tumor growth in a <a href="/facts/Dose%E2%80%93response_relationship/DLcuLdHc">dose-dependent</a> manner.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a><a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> </p><p>Clinical trials in humans began in 2010, making CK-4945 the first CK2 inhibitor to reach this stage of drug development.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a><a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> The <a href="/facts/International_Nonproprietary_Name/wYL655x6">International Nonproprietary Name</a> silmitasertib was proposed in 2010 and recommended by the <a href="/facts/World_Health_Organization/YNN3bgug">World Health Organization</a> in 2011.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a><a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> </p> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Lacey E (31 October 2022). "Owner". American Life Fund. Retrieved 19 December 2022. <a href="https://www.americanlifefund.com/financial-assistance-for-bile-duct-cancer-patients/" target="_blank">https://www.americanlifefund.com/financial-assistance-for-bile-duct-cancer-patients/</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Clinical trial number NCT03904862 for "PBTC-053: A Pediatric Brain Tumor Consortium Phase I/ II and Surgical Study of CX-4945 in Patients With Recurrent SHH Medulloblastoma" at ClinicalTrials.gov <a href="https://www.clinicaltrials.gov/show/NCT03904862" target="_blank">https://www.clinicaltrials.gov/show/NCT03904862</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Purzner T, Purzner J, Buckstaff T, Cozza G, Gholamin S, Rusert JM, et al. (September 2018). "Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma". Science Signaling. 11 (547): eaau5147. doi:10.1126/scisignal.aau5147. PMC 6475502. PMID 30206138. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475502" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475502</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Gowda C, Sachdev M, Muthusami S, Kapadia M, Petrovic-Dovat L, Hartman M, et al. (2017). "Casein Kinase II (CK2) as a Therapeutic Target for Hematological Malignancies". Current Pharmaceutical Design. 23 (1): 95–107. doi:10.2174/1381612822666161006154311. PMID 27719640. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>No authors listed (2017). "CX-4945 granted orphan drug designation". Oncology Times. 39 (5): 23. doi:10.1097/01.COT.0000514203.35081.69. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Chon HJ, Bae KJ, Lee Y, Kim J (2015). "The casein kinase 2 inhibitor, CX-4945, as an anti-cancer drug in treatment of human hematological malignancies". Frontiers in Pharmacology. 6: 70. doi:10.3389/fphar.2015.00070. PMC 4379896. PMID 25873900. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4379896" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4379896</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Siddiqui-Jain A, Drygin D, Streiner N, Chua P, Pierre F, O'Brien SE, et al. (December 2010). "CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy". Cancer Research. 70 (24): 10288–10298. doi:10.1158/0008-5472.CAN-10-1893. PMID 21159648. <a href="https://doi.org/10.1158%2F0008-5472.CAN-10-1893" target="_blank">https://doi.org/10.1158%2F0008-5472.CAN-10-1893</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Bouhaddou M, Memon D, Meyer B, White KM, Rezelj VV, Correa Marrero M, et al. (August 2020). "The Global Phosphorylation Landscape of SARS-CoV-2 Infection". Cell. 182 (3): 685–712.e19. doi:10.1016/j.cell.2020.06.034. PMC 7321036. PMID 32645325. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321036" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321036</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>"Senhwa Biosciences, NIH to co-develop COVID-19 drug". BioSpectrum. 27 April 2020. <a href="https://www.biospectrumasia.com/news/34/15848/senhwa-biosciences-nih-to-co-develop-covid-19-drug.html" target="_blank">https://www.biospectrumasia.com/news/34/15848/senhwa-biosciences-nih-to-co-develop-covid-19-drug.html</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Pierre F, Chua PC, O'Brien SE, Siddiqui-Jain A, Bourbon P, Haddach M, et al. (January 2011). "Discovery and SAR of 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the treatment of cancer". Journal of Medicinal Chemistry. 54 (2): 635–654. doi:10.1021/jm101251q. PMID 21174434. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Pierre F, Chua PC, O'Brien SE, Siddiqui-Jain A, Bourbon P, Haddach M, et al. (January 2011). "Discovery and SAR of 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the treatment of cancer". Journal of Medicinal Chemistry. 54 (2): 635–654. doi:10.1021/jm101251q. PMID 21174434. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>Siddiqui-Jain A, Drygin D, Streiner N, Chua P, Pierre F, O'Brien SE, et al. (December 2010). "CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy". Cancer Research. 70 (24): 10288–10298. doi:10.1158/0008-5472.CAN-10-1893. PMID 21159648. <a href="https://doi.org/10.1158%2F0008-5472.CAN-10-1893" target="_blank">https://doi.org/10.1158%2F0008-5472.CAN-10-1893</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Pierre F, Chua PC, O'Brien SE, Siddiqui-Jain A, Bourbon P, Haddach M, et al. (January 2011). "Discovery and SAR of 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the treatment of cancer". Journal of Medicinal Chemistry. 54 (2): 635–654. doi:10.1021/jm101251q. PMID 21174434. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>Siddiqui-Jain A, Drygin D, Streiner N, Chua P, Pierre F, O'Brien SE, et al. (December 2010). "CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy". Cancer Research. 70 (24): 10288–10298. doi:10.1158/0008-5472.CAN-10-1893. PMID 21159648. <a href="https://doi.org/10.1158%2F0008-5472.CAN-10-1893" target="_blank">https://doi.org/10.1158%2F0008-5472.CAN-10-1893</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>Pierre F, Chua PC, O'Brien SE, Siddiqui-Jain A, Bourbon P, Haddach M, et al. (January 2011). "Discovery and SAR of 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the treatment of cancer". Journal of Medicinal Chemistry. 54 (2): 635–654. doi:10.1021/jm101251q. PMID 21174434. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>World Health Organization (2010). "International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed International Nonproprietary Names: List 103" (PDF). WHO Drug Information. 24 (2): 166–167. <a href="http://apps.who.int/iris/bitstream/10665/74553/1/24_2_2010_INN103.pdf" target="_blank">http://apps.who.int/iris/bitstream/10665/74553/1/24_2_2010_INN103.pdf</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> <li id="fn:17"><p>World Health Organization (2011). "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 66" (PDF). WHO Drug Information. 25 (3): 329. <a href="https://www.who.int/medicines/publications/druginformation/innlists/RL66_final.pdf" target="_blank">https://www.who.int/medicines/publications/druginformation/innlists/RL66_final.pdf</a> <a href="#fnref:17" class="footnote-back-ref">↩</a></p></li> </ol>