Drug General Information
Drug ID	D09KTS
Drug Name	Ibrutinib
Synonyms	PCI-32765; Ibrutinib (BTK inhibitor)
Drug Type	Small molecular drug
Company	Janssen Biotech; Pharmacyclics
Structure
Drug Resistance Mutations
Target Name	Tyrosine-protein kinase BTK (BTK)				Target Info
Gene Name	BTK
Uniprot ID	BTK_HUMAN
Species	Homo sapiens
Reference Sequence	MAAVILESIFLKRSQQKKKTSPLNFKKRLFLLTVHKLSYYEYDFERGRRGSKKGSIDVEK ITCVETVVPEKNPPPERQIPRRGEESSEMEQISIIERFPYPFQVVYDEGPLYVFSPTEEL RKRWIHQLKNVIRYNSDLVQKYHPCFWIDGQYLCCSQTAKNAMGCQILENRNGSLKPGSS HRKTKKPLPPTPEEDQILKKPLPPEPAAAPVSTSELKKVVALYDYMPMNANDLQLRKGDE YFILEESNLPWWRARDKNGQEGYIPSNYVTEAEDSIEMYEWYSKHMTRSQAEQLLKQEGK EGGFIVRDSSKAGKYTVSVFAKSTGDPQGVIRHYVVCSTPQSQYYLAEKHLFSTIPELIN YHQHNSAGLISRLKYPVSQQNKNAPSTAGLGYGSWEIDPKDLTFLKELGTGQFGVVKYGK WRGQYDVAIKMIKEGSMSEDEFIEEAKVMMNLSHEKLVQLYGVCTKQRPIFIITEYMANG CLLNYLREMRHRFQTQQLLEMCKDVCEAMEYLESKQFLHRDLAARNCLVNDQGVVKVSDF GLSRYVLDDEYTSSVGSKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPYER FTNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKILLSNILDVMDEES [Homo sapiens]
Targeted Disease	Leukemia; Lymphoma
Drug Resistance Mutations	Mutation info Missense: C481S [1], [2] Mutation Frequency 2.60% of the patients
	Mutation info Missense: C481S [1], [2] Mutation Frequency 2.60% of the patients
Target Name	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 (PLCG2)				Target Info
Gene Name	PLCG2
Uniprot ID	PLCG2_HUMAN
Species	Homo sapiens
Reference Sequence	MSTTVNVDSLAEYEKSQIKRALELGTVMTVFSFRKSTPERRTVQVIMETRQVAWSKTADK IEGFLDIMEIKEIRPGKNSKDFERAKAVRQKEDCCFTILYGTQFVLSTLSLAADSKEDAV NWLSGLKILHQEAMNASTPTIIESWLRKQIYSVDQTRRNSISLRELKTILPLINFKVSSA KFLKDKFVEIGAHKDELSFEQFHLFYKKLMFEQQKSILDEFKKDSSVFILGNTDRPDASA VYLHDFQRFLIHEQQEHWAQDLNKVRERMTKFIDDTMRETAEPFLFVDEFLTYLFSRENS IWDEKYDAVDMQDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDC WDGPDGKPVIYHGWTRTTKIKFDDVVQAIKDHAFVTSSFPVILSIEEHCSVEQQRHMAKA FKEVFGDLLLTKPTEASADQLPSPSQLREKIIIKHKKLGPRGDVDVNMEDKKDEHKQQGE LYMWDSIDQKWTRHYCAIADAKLSFSDDIEQTMEEEVPQDIPPTELHFGEKWFHKKVEKR TSAEKLLQEYCMETGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEGGTLKYY LTDNLTFSSIYALIQHYRETHLRCAEFELRLTDPVPNPNPHESKPWYYDSLSRGEAEDML MRIPRDGAFLIRKREGSDSYAITFRARGKVKHCRINRDGRHFVLGTSAYFESLVELVSYY EKHSLYRKMRLRYPVTPELLERYNMERDINSLYDVSRMYVDPSEINPSMPQRTVKALYDY KAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIQQYFPSNYVEDISTADFEELEKQII EDNPLGSLCRGILDLNTYNVVKAPQGKNQKSFVFILEPKQQGDPPVEFATDRVEELFEWF QSIREITWKIDTKENNMKYWEKNQSIAIELSDLVVYCKPTSKTKDNLENPDFREIRSFVE TKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWLCGSQMVALNFQTADKY MQMNHALFSLNGRTGYVLQPESMRTEKYDPMPPESQRKILMTLTVKVLGARHLPKLGRSI ACPFVEVEICGAEYDNNKFKTTVVNDNGLSPIWAPTQEKVTFEIYDPNLAFLRFVVYEED MFSDPNFLAHATYPIKAVKSGFRSVPLKNGYSEDIELASLLVFCEMRPVLESEEELYSSC RQLRRRQEELNNQLFLYDTHQNLRNANRDALVKEFSVNENQLQLYQEKCNKRLREKRVSN SKFYS [Homo sapiens]
Targeted Disease	Leukemia; Lymphoma
Drug Resistance Mutations	Mutation info Missense: R665W [1], [3] Mutation Frequency 5.40% of the patients
	Mutation info Missense: L845F [1] Mutation Frequency 17.40% of the patients
Target Name	Myeloid differentiation primary response protein (MyD88)				Target Info
Gene Name	MYD88
Uniprot ID	MYD88_HUMAN
Species	Homo sapiens
Reference Sequence	MAAGGPGAGSAAPVSSTSSLPLAALNMRVRRRLSLFLNVRTQVAADWTALAEEMDFEYLE IRQLETQADPTGRLLDAWQGRPGASVGRLLELLTKLGRDDVLLELGPSIEEDCQKYILKQ QQEEAEKPLQVAAVDSSVPRTAELAGITTLDDPLGHMPERFDAFICYCPSDIQFVQEMIR QLEQTNYRLKLCVSDRDVLPGTCVWSIASELIEKRCRRMVVVVSDDYLQSKECDFQTKFA LSLSPGAHQKRLIPIKYKAMKKEFPSILRFITVCDYTNPCTKSWFWTRLAKALSLP [Ho mo sapiens]
Targeted Disease	Leukemia; Lymphoma
Drug Resistance Mutations	Mutation info Missense: L265P [4] Mutation Frequency 39% of the patients
Target Name	G1/S-specific cyclin D1 (CCND1)				Target Info
Gene Name	CCND1
Uniprot ID	CCND1_HUMAN
Species	Homo sapiens
Reference Sequence	MEHQLLCCEVETIRRAYPDANLLNDRVLRAMLKAEETCAPSVSYFKCVQKEVLPSMRKIV ATWMLEVCEEQKCEEEVFPLAMNYLDRFLSLEPVKKSRLQLLGATCMFVASKMKETIPLT AEKLCIYTDNSIRPEELLQMELLLVNKLKWNLAAMTPHDFIEHFLSKMPEAEENKQIIRK HAQTFVALCATDVKFISNPPSMVAAGSVVAAVQGLNLRSPNNFLSYYRLTRFLSRVIKCD PDCLRACQEQIEALLESSLRQAQQNMDPKAAEEEEEEEEEVDLACTPTDVRDVDI [Hom o sapiens]
Targeted Disease	Leukemia; Lymphoma
Drug Resistance Mutations	Mutation info Missense: C47S [5]
	Mutation info Missense: T286A [5]
	Mutation info Missense: Y44D [5]
References
REF 1	Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014 Jun 12;370(24):2286-94.
REF 2	Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition. Nat Commun. 2016 May 20;7:11589.
REF 3	Hypermorphic mutation of phospholipase C, 2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation.Blood.2015 Jul 2;126(1):61-8.
REF 4	Mechanisms of ibrutinib resistance in chronic lymphocytic leukaemia and non-Hodgkin lymphoma. Br J Haematol. 2015 Aug;170(4):445-56.
REF 5	CCND1 mutations increase protein stability and promote ibrutinib resistance in mantle cell lymphoma.Oncotarget.2016 Nov 8;7(45):73558-73572.

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