User:Fvasconcellos/CX-4945
 | |
| Clinical data | |
|---|---|
| Other names | CX-4945 |
| ATC code |
|
| Pharmacokinetic data | |
| Bioavailability | Orally bioavailable |
| Identifiers | |
| |
| CAS Number | |
| PubChem CID | |
| UNII | |
| ChEMBL | |
| PDB ligand | |
| Chemical and physical data | |
| Formula | C19H12ClN3O2 |
| Molar mass | 349.77 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
Silmitasertib (INN), codenamed CX-4945, is a small-molecule inhibitor of casein kinase II (protein kinase CK2), 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), and in pre-clinical development for other cancers, including hematological and lymphoid malignancies.[1]
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.[2]
Mechanism of action
[edit]Silmitasertib interacts competitively with the ATP-binding site of CK2 subunit alpha. This leads to inhibition of several downstream signaling pathways, including PI3K/Akt.[3][4]
History
[edit]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.[5] 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.[5]
Pre-clinical 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.[4][5]
Clinical trials in humans began in 2010, making CK-4945 the first CK2 inhibitor to reach this stage of drug development.[4][5]
References
[edit]- ^ "Casein Kinase II (CK2) as a Therapeutic Target for Hematological Malignancies". Current Pharmaceutical Design. 23 (1): 95–107. 2017. doi:10.2174/1381612822666161006154311. PMID 27719640.
{{cite journal}}: Unknown parameter|authors=ignored (help) - ^ "CX-4945 granted orphan drug designation". Oncology Times. 39 (5): 23. 2017. doi:10.1097/01.COT.0000514203.35081.69.
{{cite journal}}: Unknown parameter|authors=ignored (help) - ^ "The casein kinase 2 inhibitor, CX-4945, as an anti-cancer drug in treatment of human hematological malignancies". Frontiers in Pharmacology. 6: 70. 2015. doi:10.3389/fphar.2015.00070. PMC 4379896. PMID 25873900.
{{cite journal}}: Unknown parameter|authors=ignored (help)CS1 maint: unflagged free DOI (link) - ^ a b c "CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy". Cancer Research. 70 (24): 10288–98. 2010. doi:10.1158/0008-5472.CAN-10-1893. PMID 21159648.
{{cite journal}}: Unknown parameter|authors=ignored (help) - ^ a b c d "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): 635–54. 2011. doi:10.1021/jm101251q. PMID 21174434.
{{cite journal}}: Unknown parameter|authors=ignored (help)