Silmitasertib Explained

Iupac Name:5-[(3-chlorophenyl)amino]benzo[''c''][2,6]naphthyridine-8-carboxylic acid
Bioavailability:Orally bioavailable
Cas Number:1009820-21-6
Atc Prefix:None
Pubchem:24748573
Synonyms:CX-4945
Chemspiderid:25057795
Stdinchi:InChI=1S/C19H12ClN3O2/c20-12-2-1-3-13(9-12)22-18-15-6-7-21-10-16(15)14-5-4-11(19(24)25)8-17(14)23-18/h1-10H,(H,22,23)(H,24,25)
Stdinchikey:MUOKSQABCJCOPU-UHFFFAOYSA-N
Smiles:C1=CC(=CC(=C1)Cl)NC2=C3C=CN=CC3=C4C=CC(=CC4=N2)C(=O)O
Unii:C6RWP0N0L2
Chembl:1230165
Pdb Ligand:3NG
C:19
H:12
Cl:1
N:3
O:2

Silmitasertib (INN), codenamed CX-4945, is a small-molecule inhibitor of protein kinase CK2 (casein kinase II), a constitutively active serine/threonine-specific protein kinase that is overexpressed in several types of tumors.

Silmitasertib is in clinical trials for use as an adjunct to chemotherapy in the treatment of cholangiocarcinoma (bile duct cancer),[1] is in phase I and II clinical trials for the treatment of recurrent Sonic Hedgehog (SHH) medulloblastoma,[2] and in preclinical development for other cancers, including hematological and lymphoid malignancies.[3]

In January 2017, it was granted orphan drug status by the U.S. Food and Drug Administration for advanced cholangiocarcinoma. It is being developed by Senhwa Biosciences of Taiwan.[4]

Mechanism of action

Silmitasertib interacts competitively with the ATP-binding site of CK2 subunit alpha. This leads to inhibition of several downstream signaling pathways, including PI3K/Akt.[5] [6]

COVID-19 infections

In SARS-CoV-2 (COVID-19) infected Caco-2 cells, the phosphorylase activity of casein kinase 2 (CK2) is increased resulting in phosphorylation of several cytoskeletal proteins. These infected cells also display CK2-containing filopodia 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.[7] Senhwa Biosciences and the US National Institutes of Health have announced that they will evaluate the efficacy of silmitasertib in treating COVID-19 infections.[8]

History

CX-4945 was originated by now-defunct Cylene Pharmaceuticals of San Diego, California, as the culmination of a lengthy process of rational, structure-based molecular modification of a lead compound known to have PARP inhibitor activity.[9] Among a large series of compounds built around a benzo[''c'']-[2,6]naphthyridine-8-carboxylic acid scaffold, CX-4945 was chosen for its high potency and selectivity as an inhibitor of CK2.[9]

Preclinical pharmacokinetics studies conducted in mice, rats, and dogs confirmed that CX-4945 had satisfactory bioavailability when given by mouth and did not block cytochrome P450, while experiments in mice confirmed its inhibition of solid-tumor growth in a dose-dependent manner.[6] [9]

Clinical trials in humans began in 2010, making CK-4945 the first CK2 inhibitor to reach this stage of drug development.[6] [9] The International Nonproprietary Name silmitasertib was proposed in 2010 and recommended by the World Health Organization in 2011.[10] [11]

Notes and References

  1. Web site: Lacey E . Owner . American Life Fund . 31 October 2022 . 19 December 2022.
  2. Purzner T, Purzner J, Buckstaff T, Cozza G, Gholamin S, Rusert JM, Hartl TA, Sanders J, Conley N, Ge X, Langan M, Ramaswamy V, Ellis L, Litzenburger U, Bolin S, Theruvath J, Nitta R, Qi L, Li XN, Li G, Taylor MD, Wechsler-Reya RJ, Pinna LA, Cho YJ, Fuller MT, Elias JE, Scott MP . 6 . Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma . Science Signaling . 11 . 547 . eaau5147 . September 2018 . 30206138 . 6475502 . 10.1126/scisignal.aau5147 .
  3. Gowda C, Sachdev M, Muthusami S, Kapadia M, Petrovic-Dovat L, Hartman M, Ding Y, Song C, Payne JL, Tan BH, Dovat S . 6 . Casein Kinase II (CK2) as a Therapeutic Target for Hematological Malignancies . Current Pharmaceutical Design . 23 . 1 . 95–107 . 2017 . 27719640 . 10.2174/1381612822666161006154311 .
  4. ((No authors listed)) . CX-4945 granted orphan drug designation . Oncology Times . 39 . 5 . 23 . 2017 . 10.1097/01.COT.0000514203.35081.69.
  5. Chon HJ, Bae KJ, Lee Y, Kim J . The casein kinase 2 inhibitor, CX-4945, as an anti-cancer drug in treatment of human hematological malignancies . Frontiers in Pharmacology . 6 . 70 . 2015 . 25873900 . 4379896 . 10.3389/fphar.2015.00070 . free .
  6. Siddiqui-Jain A, Drygin D, Streiner N, Chua P, Pierre F, O'Brien SE, Bliesath J, Omori M, Huser N, Ho C, Proffitt C, Schwaebe MK, Ryckman DM, Rice WG, Anderes K . 6 . 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 . December 2010 . 21159648 . 10.1158/0008-5472.CAN-10-1893 . free .
  7. Bouhaddou M, Memon D, Meyer B, White KM, Rezelj VV, Correa Marrero M, Polacco BJ, Melnyk JE, Ulferts S, Kaake RM, Batra J, Richards AL, Stevenson E, Gordon DE, Rojc A, Obernier K, Fabius JM, Soucheray M, Miorin L, Moreno E, Koh C, Tran QD, Hardy A, Robinot R, Vallet T, Nilsson-Payant BE, Hernandez-Armenta C, Dunham A, Weigang S, Knerr J, Modak M, Quintero D, Zhou Y, Dugourd A, Valdeolivas A, Patil T, Li Q, Hüttenhain R, Cakir M, Muralidharan M, Kim M, Jang G, Tutuncuoglu B, Hiatt J, Guo JZ, Xu J, Bouhaddou S, Mathy CJ, Gaulton A, Manners EJ, Félix E, Shi Y, Goff M, Lim JK, McBride T, O'Neal MC, Cai Y, Chang JC, Broadhurst DJ, Klippsten S, De Wit E, Leach AR, Kortemme T, Shoichet B, Ott M, Saez-Rodriguez J, tenOever BR, Mullins RD, Fischer ER, Kochs G, Grosse R, García-Sastre A, Vignuzzi M, Johnson JR, Shokat KM, Swaney DL, Beltrao P, Krogan NJ . 6 . The Global Phosphorylation Landscape of SARS-CoV-2 Infection . Cell . 182 . 3 . 685–712.e19 . August 2020 . 32645325 . 7321036 . 10.1016/j.cell.2020.06.034 . free .
  8. Web site: Senhwa Biosciences, NIH to co-develop COVID-19 drug . BioSpectrum . 27 April 2020 .
  9. Pierre F, Chua PC, O'Brien SE, Siddiqui-Jain A, Bourbon P, Haddach M, Michaux J, Nagasawa J, Schwaebe MK, Stefan E, Vialettes A, Whitten JP, Chen TK, Darjania L, Stansfield R, Anderes K, Bliesath J, Drygin D, Ho C, Omori M, Proffitt C, Streiner N, Trent K, Rice WG, Ryckman DM . 6 . 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 . January 2011 . 21174434 . 10.1021/jm101251q .
  10. International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed International Nonproprietary Names: List 103 . WHO Drug Information . 24 . 2 . 2010 . ((World Health Organization)) . 166–167 .
  11. International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 66 . WHO Drug Information . 25 . 3 . 2011 . ((World Health Organization)) . 329 .

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