Drug General Information
Drug ID	D05ROI
Drug Name	Dabrafenib
Synonyms	1195765-45-7; Dabrafenib (GSK2118436); Tafinlar; GSK2118436A; UNII-QGP4HA4G1B; GSK 2118436; QGP4HA4G1B; N-(3-(5-(2-aminopyrimidin-4-yl)-2-tert-butylthiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide; CHEBI:75045; N-[3-[5-(2-Amino-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide; N-{3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide; GSK-2118436A; Dabrafenib [USAN:INN]; GSK2118436
Drug Type	Small molecular drug
Structure
Drug Resistance Mutations
Target Name	GTPase Nras (NRAS)				Target Info
Gene Name	NRAS
Uniprot ID	RASN_HUMAN
Species	Homo sapiens
Reference Sequence	MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAG QEEYSAMRDQYMRTGEGFLCVFAINNSKSFADINLYREQIKRVKDSDDVPMVLVGNKCDL PTRTVDTKQAHELAKSYGIPFIETSAKTRQGVEDAFYTLVREIRQYRMKKLNSSDDGTQG CMGLPCVVM [Homo sapiens]
Targeted Disease	Skin cancer
Drug Resistance Mutations	Mutation info Missense: Q61K [1] Mutation Frequency 4 out of 76 patients
	Mutation info Missense: G12D [4] Mutation Frequency 1 out of 10 patients
Target Name	Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2)				Target Info
Gene Name	MAP2K2
Uniprot ID	MP2K2_HUMAN
Species	Homo sapiens
Reference Sequence	MLARRKPVLPALTINPTIAEGPSPTSEGASEANLVDLQKKLEELELDEQQKKRLEAFLTQ KAKVGELKDDDFERISELGAGNGGVVTKVQHRPSGLIMARKLIHLEIKPAIRNQIIRELQ VLHECNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKEAKRIPEEILGKVSIAVLRG LAYLREKHQIMHRDVKPSNILVNSRGEIKLCDFGVSGQLIDSMANSFVGTRSYMAPERLQ GTHYSVQSDIWSMGLSLVELAVGRYPIPPPDAKELEAIFGRPVVDGEEGEPHSISPRPRP PGRPVSGHGMDSRPAMAIFELLDYIVNEPPPKLPNGVFTPDFQEFVNKCLIKNPAERADL KMLTNHTFIKRSEVEEVDFAGWLCKTLRLNQPGTPTRTAV [Homo sapiens]
Targeted Disease	Skin cancer
Drug Resistance Mutations	Mutation info Missense: Q60P [2], [3] Mutation Frequency 3 out of 5 patients
	Mutation info Missense: C125S [1], [4] Mutation Frequency 2 out of 10 patients
	Mutation info Missense: V35M [1]
	Mutation info Missense: N126D [1] Mutation Frequency 1 out of 76 patients
	Mutation info Missense: L46F [1] Mutation Frequency 3 out of 76 patients
	Mutation info Missense: E207K [4] Mutation Frequency 1 out of 10 patients
Target Name	Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1)				Target Info
Gene Name	MAP2K1
Uniprot ID	MP2K1_HUMAN
Species	Homo sapiens
Reference Sequence	MPKKKPTPIQLNPAPDGSAVNGTSSAETNLEALQKKLEELELDEQQRKRLEAFLTQKQKV GELKDDDFEKISELGAGNGGVVFKVSHKPSGLVMARKLIHLEIKPAIRNQIIRELQVLHE CNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKKAGRIPEQILGKVSIAVIKGLTYL REKHKIMHRDVKPSNILVNSRGEIKLCDFGVSGQLIDSMANSFVGTRSYMSPERLQGTHY SVQSDIWSMGLSLVEMAVGRYPIPPPDAKELELMFGCQVEGDAAETPPRPRTPGRPLSSY GMDSRPPMAIFELLDYIVNEPPPKLPSGVFSLEFQDFVNKCLIKNPAERADLKQLMVHAF IKRSDAEEVDFAGWLCSTIGLNQPSTPTHAAGV [Homo sapiens]
Targeted Disease	Skin cancer
Drug Resistance Mutations	Mutation info Missense: P124S [1] Mutation Frequency 1 out of 76 patients
	Mutation info Missense: G128D [4] Mutation Frequency 1 out of 10 patients
	Mutation info Missense: K57E [7] Mutation Frequency 1 out of 30 patients
Target Name	RAC-alpha serine/threonine-protein kinase (AKT1)				Target Info
Gene Name	AKT1
Uniprot ID	AKT1_HUMAN
Species	Homo sapiens
Reference Sequence	MSDVAIVKEGWLHKRGEYIKTWRPRYFLLKNDGTFIGYKERPQDVDQREAPLNNFSVAQC QLMKTERPRPNTFIIRCLQWTTVIERTFHVETPEEREEWTTAIQTVADGLKKQEEEEMDF RSGSPSDNSGAEEMEVSLAKPKHRVTMNEFEYLKLLGKGTFGKVILVKEKATGRYYAMKI LKKEVIVAKDEVAHTLTENRVLQNSRHPFLTALKYSFQTHDRLCFVMEYANGGELFFHLS RERVFSEDRARFYGAEIVSALDYLHSEKNVVYRDLKLENLMLDKDGHIKITDFGLCKEGI KDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFEL ILMEEIRFPRTLGPEAKSLLSGLLKKDPKQRLGGGSEDAKEIMQHRFFAGIVWQHVYEKK LSPPFKPQVTSETDTRYFDEEFTAQMITITPPDQDDSMECVDSERRPHFPQFSYSASGTA [Homo sapiens]
Targeted Disease	Skin cancer
Drug Resistance Mutations	Mutation info Missense: E17K [5]
	Mutation info Missense: Q79K [5]
Target Name	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA)				Target Info
Gene Name	PIK3CA
Uniprot ID	PK3CA_HUMAN
Species	Homo sapiens
Reference Sequence	MPPRPSSGELWGIHLMPPRILVECLLPNGMIVTLECLREATLITIKHELFKEARKYPLHQ LLQDESSYIFVSVTQEAEREEFFDETRRLCDLRLFQPFLKVIEPVGNREEKILNREIGFA IGMPVCEFDMVKDPEVQDFRRNILNVCKEAVDLRDLNSPHSRAMYVYPPNVESSPELPKH IYNKLDKGQIIVVIWVIVSPNNDKQKYTLKINHDCVPEQVIAEAIRKKTRSMLLSSEQLK LCVLEYQGKYILKVCGCDEYFLEKYPLSQYKYIRSCIMLGRMPNLMLMAKESLYSQLPMD CFTMPSYSRRISTATPYMNGETSTKSLWVINSALRIKILCATYVNVNIRDIDKIYVRTGI YHGGEPLCDNVNTQRVPCSNPRWNEWLNYDIYIPDLPRAARLCLSICSVKGRKGAKEEHC PLAWGNINLFDYTDTLVSGKMALNLWPVPHGLEDLLNPIGVTGSNPNKETPCLELEFDWF SSVVKFPDMSVIEEHANWSVSREAGFSYSHAGLSNRLARDNELRENDKEQLKAISTRDPL SEITEQEKDFLWSHRHYCVTIPEILPKLLLSVKWNSRDEVAQMYCLVKDWPPIKPEQAME LLDCNYPDPMVRGFAVRCLEKYLTDDKLSQYLIQLVQVLKYEQYLDNLLVRFLLKKALTN QRIGHFFFWHLKSEMHNKTVSQRFGLLLESYCRACGMYLKHLNRQVEAMEKLINLTDILK QEKKDETQKVQMKFLVEQMRRPDFMDALQGFLSPLNPAHQLGNLRLEECRIMSSAKRPLW LNWENPDIMSELLFQNNEIIFKNGDDLRQDMLTLQIIRIMENIWQNQGLDLRMLPYGCLS IGDCVGLIEVVRNSHTIMQIQCKGGLKGALQFNSHTLHQWLKDKNKGEIYDAAIDLFTRS CAGYCVATFILGIGDRHNSNIMVKDDGQLFHIDFGHFLDHKKKKFGYKRERVPFVLTQDF LIVISKGAQECTKTREFERFQEMCYKAYLAIRQHANLFINLFSMMLGSGMPELQSFDDIA YIRKTLALDKTEQEALEYFMKQMNDAHHGGWTTKMDWIFHTIKQHALN [Homo sapie ns]
Targeted Disease	Skin cancer
Drug Resistance Mutations	Mutation info Missense: E545* [6]
References
REF 1	The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 2014 Jan;4(1):94-109.
REF 2	MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. Cancer Discov. 2014 Jan;4(1):61-8.
REF 3	Co-clinical assessment identifies patterns of BRAF inhibitor resistance in melanoma. J Clin Invest. 2015 Apr;125(4):1459-70.
REF 4	Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma. Nat Commun. 2014 Dec 2;5:5694.
REF 5	A novel AKT1 mutant amplifies an adaptive melanoma response to BRAF inhibition. Cancer Discov. 2014 Jan;4(1):69-79.
REF 6	Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014 Jan;4(1):80-93.
REF 7	BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin Cancer Res. 2014 Apr 1;20(7):1965-77.

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