Resistance mutation info of drug

Drug General Information
Drug ID D09KTS
Drug Name Ibrutinib Drug Info
Synonyms PCI-32765
Drug Type Small molecular drug
Company Janssen Biotech; Pharmacyclics
Structure D09KTS
Drug Resistance Mutations
Target Name 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 (PLCG2)
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 Refractory hematologic malignancy
Drug Resistance Mutations
Mutation info Missense: R665W [556014], [1559273]
Mutation Prevalence 5.40% of the patients
Mutation info Missense: L845F [556014]
Mutation Prevalence 17.40% 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 Refractory hematologic malignancy
Drug Resistance Mutations
Mutation info Missense: C47S [1559235]
Mutation info Missense: T286A [1559235]
Mutation info Missense: Y44D [1559235]
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 Refractory hematologic malignancy
Drug Resistance Mutations
Mutation info Missense: L265P [556057]
Mutation Prevalence 39% of the patients
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 Refractory hematologic malignancy
Drug Resistance Mutations
Mutation info Missense: C481S [556014], [556126]
Mutation Prevalence 2.60% of the patients
Mutation info Missense: C481S [556014], [556126]
Mutation Prevalence 2.60% of the patients
References
Ref 524263ClinicalTrials.gov (NCT01833039) An Open Label Treatment Use Protocol for Ibrutinib in Subjects With Relapsed or Refractory Mantle Cell Lymphoma. U.S. National Institutes of Health.
Ref 541962(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6912).
Ref 551043Janssen's IMBRUVICA (ibrutinib) Receives Additional European Commission Approval for the Treatment of Waldenstrom's Macroglobulinemia. Janssen-Cilag International NV (Janssen). Jul 10, 2015.
Ref 556014Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014 Jun 12;370(24):2286-94. doi: 10.1056/NEJMoa1400029. Epub 2014 May 28.
Ref 556057Mechanisms of ibrutinib resistance in chronic lymphocytic leukaemia and non-Hodgkin lymphoma. Br J Haematol. 2015 Aug;170(4):445-56. doi: 10.1111/bjh.13427. Epub 2015 Apr 9.
Ref 556126Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition. Nat Commun. 2016 May 20;7:11589. doi: 10.1038/ncomms11589.
Ref 1559273Hypermorphic 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 1559235CCND1 mutations increase protein stability and promote ibrutinib resistance in mantle cell lymphoma.Oncotarget.2016 Nov 8;7(45):73558-73572.

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