Chemistry:Agerafenib
Agerafenib is a selective multi-kinase inhibitor. It is undergoing a trial to test its ability to treat malignant tumors in humans. It is effective in doses ranging between 30 milligrams and 100 milligrams. It is also known as CEP-32496 and RXDX 105. It is a strong inhibitor of the BRAF gene that is commonly found in cancerous cells.
Discovery
Agerafenib was originally discovered by a company called Daiichi Sankyo (then called Ambit Biosciences) and Teva Pharmaceuticals (then called Cephalon) during a research program.[1] The chemical was originally named "CEP-32496" before being renamed to "RXDX 105" in 2015.[1] It is currently undergoing a clinical trial to test its effectiveness against cancer in humans.[2]
Characteristics
Agerafenib's chemical formula consists of 24 carbon atoms, 22 hydrogen atoms, 3 fluorine atoms, 5 nitrogen atoms and 5 oxygen atoms.[3] The chemical's molar mass is 517.465 g/mol, and the monoisotopic mass is 517.157303 g/mol.[4] It appears as a white to off-white crystalline powder in room temperature.[5] Agerafenib has 5 hydrogen bond acceptors and 2 hydrogen bond donors.[6] It has an partition coefficient of 4.35. It has 10 rotatable bonds and a topological polar surface area of 120.63.[6]
The chemical is a strong inhibitor of the BRAF gene, which is present in around 7% of all malignant tumors.[7] It does this due to its strong cytotoxicity to cells containing it.[7] Agerafenib also inhibits phosphorylation in mitogen-activated protein kinase (an enzyme that causes certain cellular responses).[8] The drug is shown to be most effective in humans in doses between 30 milligrams and 100 milligrams.[9]
References
- ↑ 1.0 1.1 "NCATS Inxight Drugs — AGERAFENIB" (in en). https://drugs.ncats.io/drug/78I4VEX88N.
- ↑ "Agerafenib" (in en). https://go.drugbank.com/drugs/DB15068.
- ↑ "CEP-32496" (in en). https://www.glpbio.com/cep-32496.html.
- ↑ "Comptox – 1-[3-(6,7-dimethoxyquinazolin-4-yl)oxyphenyl-3-[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]urea"]. https://comptox.epa.gov/dashboard/chemical/details/DTXSID601025976.
- ↑ Ruggeri, B.; Wabler, M.; Bruckheimer, E.; Wilkinson, B.; Dorsey, B.; Trusko, S.; Friedman, J. (2014). "471 Screening of Champions predictive TumorGraft platform guides the clinical development of the selective dual BRAF-EGFR inhibitor CEP-32496" (in en). European Journal of Cancer 50: 154. doi:10.1016/S0959-8049(14)70597-0. https://linkinghub.elsevier.com/retrieve/pii/S0959804914705970.
- ↑ 6.0 6.1 "agerafenib | Ligand page | IUPHAR/BPS Guide to PHARMACOLOGY". https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7880.
- ↑ 7.0 7.1 James, Joyce; Ruggeri, Bruce; Armstrong, Robert C.; Rowbottom, Martin W.; Jones-Bolin, Susan; Gunawardane, Ruwanthi N.; Dobrzanski, Pawel; Gardner, Michael F. et al. (2012-04-01). "CEP-32496: A Novel Orally Active BRAFV600E Inhibitor with Selective Cellular and In Vivo Antitumor Activity" (in en). Molecular Cancer Therapeutics 11 (4): 930–941. doi:10.1158/1535-7163.MCT-11-0645. ISSN 1535-7163. PMID 22319199. https://aacrjournals.org/mct/article/11/4/930/91257/CEP-32496-A-Novel-Orally-Active-BRAFV600E.
- ↑ Jiang, Cuiping; Xie, Lin; Zhang, Yiding; Fujinaga, Masayuki; Mori, Wakana; Kurihara, Yusuke; Yamasaki, Tomoteru; Wang, Feng et al. (2018-01-01). "Pharmacokinetic Evaluation of [ 11 CCEP-32496 in Nude Mice Bearing BRAF V600E Mutation-Induced Melanomas"] (in en). Molecular Imaging 17. doi:10.1177/1536012118795952. ISSN 1535-3508. PMID 30251592.
- ↑ Purich, Daniel (2017). The Inhibitor Index: A Desk Reference on Enzyme Inhibitors, Receptor Antagonists, Drugs, Toxins, Poisons, Biologics, and Therapeutic Leads. London: CRC Press. pp. 1989. ISBN 978-1-351-73067-9.
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