32421PathwayNilotinib Inhibition of BCR-ABLNilotinib is a tyrosine kinase inhibitor used to treat chronic myelogenous leukemia (CML), a cancer characterized by increased and unregulated growth of white blood cells in the bone marrow and the accumulation of these cells in the blood. The cause of CML pathophysiology is the BCR-ABL fusion protein - the result of a genetic abnormality known as the Philadelphia chromosome in which Abelson Murine Leukemia viral oncogene homolog 1 (ABL1) translocates within the Breakpoint Cluster Region (BCR) gene on chromosome 22. BCR-ABL is a cytoplasm-targeted constitutively active tyrosine kinase that activates several oncogenic pathways which promote increased cell proliferation and survival including the MAPK/ERK Pathway, the JAK-STAT Pathway, and the PI3K/Akt pathway. Nilotinib is considered a second generation BCR-ABL inhibitor (Imatinib being the progenitor) that inhibits BCR-ABL activity by binding a highly conserved ATP binding site to effectively lock the tyrosine kinase in an inactive conformation. As a result, phosphate is unable to be transferred from ATP to activate oncogenic signalling cascades. For greater detail, refer to the pathway titled BCR-ABL Action in CML Pathogenesis. Nilotinib is able to bind ABL with greater affinity than Imatinib (20-fold to 30-fold increase). It is therefore administered to patients with Imatinib resistance. Notably, Nilotinib is ineffective against the T315I mutation in BCR-ABL, and further research is necessary.Drug ActionPW032595CenterPathwayVisualizationContext3287524502608#FFFFFFPathwayVisualization3234732421Nilotinib Inhibition of BCR-ABLNilotinib is a tyrosine kinase inhibitor used to treat chronic myelogenous leukemia (CML), a cancer characterized by increased and unregulated growth of white blood cells in the bone marrow and the accumulation of these cells in the blood. The cause of CML pathophysiology is the BCR-ABL fusion protein - the result of a genetic abnormality known as the Philadelphia chromosome in which Abelson Murine Leukemia viral oncogene homolog 1 (ABL1) translocates within the Breakpoint Cluster Region (BCR) gene on chromosome 22. BCR-ABL is a cytoplasm-targeted constitutively active tyrosine kinase that activates several oncogenic pathways which promote increased cell proliferation and survival including the MAPK/ERK Pathway, the JAK-STAT Pathway, and the PI3K/Akt pathway. Nilotinib is considered a second generation BCR-ABL inhibitor (Imatinib being the progenitor) that inhibits BCR-ABL activity by binding a highly conserved ATP binding site to effectively lock the tyrosine kinase in an inactive conformation. As a result, phosphate is unable to be transferred from ATP to activate oncogenic signalling cascades. For greater detail, refer to the pathway titled BCR-ABL Action in CML Pathogenesis. Nilotinib is able to bind ABL with greater affinity than Imatinib (20-fold to 30-fold increase). It is therefore administered to patients with Imatinib resistance. Notably, Nilotinib is ineffective against the T315I mutation in BCR-ABL, and further research is necessary.Drug18245117853901Quintas-Cardama A, Kantarjian H, Cortes J: Flying under the radar: the new wave of BCR-ABL inhibitors. Nat Rev Drug Discov. 2007 Oct;6(10):834-48. doi: 10.1038/nrd2324.32421Pathway8245221098337O'Hare T, Deininger MW, Eide CA, Clackson T, Druker BJ: Targeting the BCR-ABL signaling pathway in therapy-resistant Philadelphia chromosome-positive leukemia. Clin Cancer Res. 2011 Jan 15;17(2):212-21. doi: 10.1158/1078-0432.CCR-09-3314. Epub 2010 Nov 22.32421Pathway8245322156549Cilloni D, Saglio G: Molecular pathways: BCR-ABL. Clin Cancer Res. 2012 Feb 15;18(4):930-7. doi: 10.1158/1078-0432.CCR-10-1613. Epub 2011 Dec 8.32421Pathway1CellCL:00000004Cardiomyocyte CL:00007461Homo sapiens9606EukaryoteHuman4Arabidopsis thaliana3702EukaryoteThale cress6Caenorhabditis elegans6239EukaryoteRoundworm5CytoplasmGO:00057371CytosolGO:000582919sarcoplasmic reticulumGO:001652925Golgi ApparatusGO:000579410Cell MembraneGO:000588615NucleusGO:000563411Extracellular SpaceGO:00056155cardiocyteBTO:000153924BrainBTO:000014289168511PW_BS0000082111PW_BS0000023551914PW_BS000035432511PW_BS0000431644PW_BS00016414101PW_BS000014209106PW_BS000024231511PW_BS00002327151PW_BS000027711PW_BS000007151141PW_BS0001518424111PW_BS0000849853NilotinibHMDB0015595Nilotinib, also known as AMN107, is a tyrosine kinase inhibitor under investigation as a possible treatment for chronic myelogenous leukemia (CML). In June 2006, a Phase I clinical trial found nilotinib has a relatively favorable safety profile and shows activity in cases of CML resistant to treatment with imatinib (Gleevec®), another tyrosine kinase inhibitor currently used as a first-line treatment. [Wikipedia]641571-10-064424152172559260DB04868CC1=CN(C=N1)C1=CC(=CC(NC(=O)C2=CC(NC3=NC=CC(=N3)C3=CN=CC=C3)=C(C)C=C2)=C1)C(F)(F)FC28H22F3N7OInChI=1S/C28H22F3N7O/c1-17-5-6-19(10-25(17)37-27-33-9-7-24(36-27)20-4-3-8-32-14-20)26(39)35-22-11-21(28(29,30)31)12-23(13-22)38-15-18(2)34-16-38/h3-16H,1-2H3,(H,35,39)(H,33,36,37)HHZIURLSWUIHRB-UHFFFAOYSA-N4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}benzamide529.5158529.183792976-5.422nilotinib00Amn-107;Amn107;Amn 107;NilotinibumPW_C009853Nilot438278338RasProteinComplex955ProteinComplexPW_EC000337ChEBIRas800688342AktProteinComplex982ProteinComplexPW_EC000342Akt339RAFProteinComplex1030ProteinComplexPW_EC000339RAF800698340MEKProteinComplex1031ProteinComplexPW_EC000340MEK341MAPKProteinComplex948ProteinComplexPW_EC000341MAPK343FOXOProteinComplex6625ProteinComplexPW_EC000343FOXO13539Bcr-abl1 fusion proteinA8E194Bcr-abl1 fusion protein is a cytoplasm-targeted constitutively active tyrosine kinase that causes uninhibited cell proliferation. This fusion protein is the result of Abelson Murine Leukemia viral oncogene homolog 1 (ABL1) translocating within the Breakpoint Cluster Region (BCR) gene on chromosome 22 and is necessary for Chronic Myeloid Leukemia (CML) pathogenesis.BCR-ABL114379785154Growth factor receptor-bound protein 2P62993Isoform GRB3-3 does not bind to phosphorylated epidermal growth factor receptor (EGFR) but inhibits EGF-induced transactivation of a RAS-responsive element. Isoform GRB3-3 acts as a dominant negative protein over GRB2 and by suppressing proliferative signals, may trigger active programmed cell deathHMDBP11487GRB217q24-q25AF063614142312655335116548139602435783GRB2-associated-binding protein 2Q9UQC2Adapter protein which acts downstream of several membrane receptors including cytokine, antigen, hormone, cell matrix and growth factor receptors to regulate multiple signaling pathways. Regulates osteoclast differentiation mediating the TNFRSF11A/RANK signaling. In allergic response, it plays a role in mast cells activation and degranulation through PI-3-kinase regulation. Also involved in the regulation of cell proliferation and hematopoiesis.GAB21421624380983798Son of sevenless homolog 1Q07889Promotes the exchange of Ras-bound GDP by GTPHMDBP08580SOS12p21L138571423221165588566Adapter molecule crkP46108
The Crk-I and Crk-II forms differ in their biological activities. Crk-II has less transforming activity than Crk-I. Crk-II mediates attachment-induced MAPK8 activation, membrane ruffling and cell motility in a Rac-dependent manner. Involved in phagocytosis of apoptotic cells and cell motility via its interaction with DOCK1 and DOCK4. May regulate the EFNA5-EPHA3 signaling.
CRK14381088618Crk-like proteinP46109
May mediate the transduction of intracellular signals.
CRKL14381182779E3 ubiquitin-protein ligase CBLP22681Participates in signal transduction in hematopoietic cells. Adapter protein that functions as a negative regulator of many signaling pathways that start from receptors at the cell surface. Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Recognizes activated receptor tyrosine kinases, including PDGFA, EGF and CSF1, and terminates signalingHMDBP07558CBL11q23.3BC13273316.3.2.-92701644381282388Phosphatidylinositol 3-kinase regulatory subunit alphaP27986Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissuesHMDBP03978PIK3R15q13.1AF279367125281425702116658802232099530Signal transducer and activator of transcription 5AP42229
Carries out a dual function: signal transduction and activation of transcription. Mediates cellular responses to the cytokine KITLG/SCF and other growth factors. Mediates cellular responses to ERBB4. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4. Binds to the GAS element and activates PRL-induced transcription. Regulates the expression of milk proteins during lactation.
STAT5A14381388059223889941489156279422971121Tyrosine-protein kinase JAK2O60674Non-receptor tyrosine kinase involved in various processes such as cell cycle progression, apoptosis, mitotic recombination, genetic instability and histone modifications. In the cytoplasm, plays a pivotal role in signal transduction via its association with cytokine receptors, which constitutes an initiating step in signaling for many members of the cytokine receptor superfamily including the receptors for growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), granulocyte-macrophage colony-stimulating factor (CSF2), thrombopoietin (THPO) and multiple interleukins. Following stimulation with erythropoietin (EPO) during erythropoiesis, it is autophosphorylated and activated, leading to its association with erythropoietin receptor (EPOR) and tyrosine phosphorylation of residues in the EPOR cytoplasmic domain. Also involved in promoting the localization of EPOR to the plasma membrane. Also acts downstream of some G-protein coupled receptors. Plays a role in the control of body weight. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatinHMDBP01194JAK29p24AF05892512.7.10.243814888997148506S-phase kinase-associated protein 2Q13309
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins involved in cell cycle progression, signal transduction and transcription. Specifically recognizes phosphorylated CDKN1B/p27kip and is involved in regulation of G1/S transition. Degradation of CDKN1B/p27kip also requires CKS1. Recognizes target proteins ORC1, CDT1, RBL2, KMT2A/MLL1, CDK9, RAG2, FOXO1, UBP43, and probably MYC, TOB1 and TAL1. Degradation of TAL1 also requires STUB1. Recognizes CDKN1A in association with CCNE1 or CCNE2 and CDK2. Promotes ubiquitination and destruction of CDH1 in a CK1-Dependent Manner, thereby regulating cell migration.
SKP214381589228Cyclin-dependent kinase inhibitor 1BP46527
Important regulator of cell cycle progression. Involved in G1 arrest. Potent inhibitor of cyclin E- and cyclin A-CDK2 complexes. Forms a complex with cyclin type D-CDK4 complexes and is involved in the assembly, stability, and modulation of CCND1-CDK4 complex activation. Acts either as an inhibitor or an activator of cyclin type D-CDK4 complexes depending on its phosphorylation state and/or stoichometry.
CDKN1B143816232017Serine/threonine-protein kinase mTORP42345Kinase subunit of both mTORC1 and mTORC2, which regulate cell growth and survival in response to nutrient and hormonal signals. mTORC1 is activated in response to growth factors or amino-acids. Amino-acid-signaling to mTORC1 is mediated by Rag GTPases, which cause amino-acid-induced relocalization of mTOR within the endomembrane system. Growth factor-stimulated mTORC1 activation involves AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-421', which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. mTORC2 is also activated by growth factors, but seems to be nutrient- insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'HMDBP02611MTOR1p36.2U8896612.7.11.1504424381781354871511325Ribosomal protein S6 kinase beta-1P23443Acts to integrate nutrient and growth factor signals in regulation of protein synthesis, cell proliferation, cell growth, cell cycle progression and cell survival. Downstream effector of the mTOR signaling pathway. Phosphorylates specifically ribosomal protein S6 in response to insulin or several classes of mitogens. During translation initiation, the inactive form associatess with the eIF-3 complex under conditions of nutrient depletion. Mitogenic stimulation leads to phosphorylation and dissociation from the eIF-3 complex and the free activated form can phosphorylate other translational targets including EIF4B. Promotes protein synthesis by phosphorylating PDCD4 at 'Ser-67' and targeting it for degradation. Phosphorylates RICTOR leading to regulation of mammalian target of rapamycin complex 2 (mTORC2) signaling; probably phosphorylates RICTOR at 'Thr-1135'. Phosphorylates IRS1 at multiple serine residues coupled with insulin resistance; probably phosphorylates IRS1 at 'Ser-270'. Required for TNF-alpha induced IRS-1 degradation. Phosphorylates EEF2K in response to IGF1 and inhibits EEF2K activity. Phosphorylates BAD at 'Ser-99' in response to IGF1 leading to BAD inactivation and inhibition of BAD-induced apoptosis. Phosphorylates mitochondrial RMP leading to dissociation of a RMP:PPP1CC complex; probably phosphorylates RMP at 'Ser-99'. The free mitochondrial PPP1CC can dephosphorylate RPS6KB1 at Thr-412 which is proposed to be a negative feed back mechanism for the RPS6KB1 antiapoptotic function. Phosphorylates GSK3B at 'Ser-9' under conditions leading to loss of the TSC1-TSC2 complex. Phosphorylates POLDIP3HMDBP01426RPS6KB117q23.1M6072412.7.11.1504524381885772Bcl2-associated agonist of cell deathQ92934Promotes cell death. Successfully competes for the binding to Bcl-X(L), Bcl-2 and Bcl-W, thereby affecting the level of heterodimerization of these proteins with BAX. Can reverse the death repressor activity of Bcl-X(L), but not that of Bcl-2 (By similarity). Appears to act as a link between growth factor receptor signaling and the apoptotic pathwaysBAD1412624381989121Bcl-2-like protein 1Q07817
Potent inhibitor of cell death. Inhibits activation of caspases. Appears to regulate cell death by blocking the voltage-dependent anion channel (VDAC) by binding to it and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. Also acts as a regulator of G2 checkpoint and progression to cytokinesis during mitosis.
BCL2L114382081940E3 ubiquitin-protein ligase Mdm2Q00987E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degration by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as an ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of TP53/p53. Promotes proteasome-dependent ubiquitin- independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradationHMDBP02432MDM212q14.3-q15M9242416.3.2.-4382185728Cellular tumor antigen p53P04637TP53AY27015513138261908443822238023888433Myc proto-oncogene proteinP01106
Transcription factor that binds DNA in a non-specific manner, yet also specifically recognizes the core sequence 5'-CAC[GA]TG-3'. Activates the transcription of growth-related genes.
MYC143823236622BCR-ABL/GRB2/GAB2/SOS1 complex1PW_P00662214353135391435451541435557831435637984379886623BCR-ABL/CRK/CRKL/CBL/PI3K complex1PW_P00662314357135391435885661435986181436027791436123884380083177STAT5A homodimer complex1PW_P0031779103953016629Tyrosine-protein kinase JAK21PW_P0066291436711214380686626S-phase kinase-associated protein 21PW_P0066261436485064380386627cyclin-dependent kinase inhibitor 1B1PW_P0066271436592284380481125Serine/threonine-protein kinase mTOR1PW_P001125128720171112670 kDa ribosomal protein S6 kinase1PW_P001126128813251980Bcl2-associated agonist of cell death1PW_P0009801106577216628Bcl-2-like protein 11PW_P0066281436691214380586621E3 ubiquitin-protein ligase Mdm21PW_P0066211435219404379623762Cellular tumor antigen p531PW_P00076285957286630Myc proto-oncogene protein1PW_P00663014368843343807236631BCR-ABL1PW_P0066311436913539438248213ActivationPW_I0002134256622ProteinComplex1426338ElementCollection1217ActivationPW_I0002174336622ProteinComplex14346623ProteinComplex1218ActivationPW_I0002184356623ProteinComplex1436342ElementCollection1228ActivationPW_I0002284556622ProteinComplex14563177ProteinComplex1229ActivationPW_I0002294576622ProteinComplex14586629ProteinComplex1230ActivationPW_I0002304596629ProteinComplex14603177ProteinComplex1214ActivationPW_I000214427338ElementCollection1428339ElementCollection1215ActivationPW_I000215429339ElementCollection1430340ElementCollection1216ActivationPW_I000216431340ElementCollection1432341ElementCollection1219InhibitionPW_I000219437342ElementCollection1438343ElementCollection1220ActivationPW_I000220439342ElementCollection14406626ProteinComplex1221InhibitionPW_I0002214416626ProteinComplex14426627ProteinComplex1222ActivationPW_I000222443342ElementCollection14441125ProteinComplex1223ActivationPW_I0002234451125ProteinComplex14461126ProteinComplex1224InhibitionPW_I000224447342ElementCollection1448980ProteinComplex1225InhibitionPW_I000225449980ProteinComplex14506628ProteinComplex1226ActivationPW_I000226451342ElementCollection14526621ProteinComplex1227InhibitionPW_I0002274536621ProteinComplex1454762ProteinComplex1231ActivationPW_I0002314616629ProteinComplex14626630ProteinComplex1234InhibitionPW_I0002344679853Compound14686631ProteinComplex187565398538157false114621510regular20019087653381448false111876512regular1507087663421448false171876012regular1507087673391448false111891512regular1507087683401448false1118106512regular1507087693411448false1118121512regular1507087703431448false1718101512regular150703881651353982true6584158generegular15070388166515482false10335208generegular15070388167578382false10435758generegular15070388168379882false9235558generegular150703881691353982true14034058subunitregular15070388170856682false13435609generegular15070388171861882false14385358generegular15070388172277982false13135158generegular15070388173238882false141860010generegular15070388174953082false7239958generegular15070388175112182false9238408generegular15070388176850682false132316158generegular150703881779228232false132317608generegular15070388178201782false151810158generegular15070388179132582false151812158generegular15070388180577282false191810158generegular15070388181912182false191816158generegular15070388182194082false212310158generegular150703881835728232false212316158generegular150703881848433232false91816158generegular15070388185135398116false11665108generegular160802775506622323478387072388165387073388166387074388167387075388168277551662332347838707638816938707738817038707838817138707938817238708038817327755231773234783870813881742775536629323478387082388175277554662632347838708338817627755566273234723387084388177277556112532347838708538817827755711263234783870863881792775589803234783870873881802775596628323478387088388181277560662132347838708938818227756176232347233870903881832775626630323472338709138818427756366313234783870923881851242333M1193 765 C1146 730 1040 652 998 625 149false18trueM 418.94685504416486 13.26155629629604 L 404 12 L 410.38088772118584 25.575134323078345false1242334M998 625 C998 655 1305 673 1305 703 149true181242335M1193 610 C1223 610 1388 635 1418 635 149false18trueM 1415.0096189432334 402.5 L 1428 395 L 1415.0096189432334 387.5false1242336M1823 765 C1793 765 1223 610 1193 610 149true18trueM 348.94685504416486 13.26155629629604 L 334 12 L 340.38088772118584 25.575134323078345false1242337M1793 760 C1721 742 1540 684 1493 670 149false18trueM 576.9468550441649 102.26155629629604 L 562 101 L 568.3808877211858 114.57513432307834false1242338M1493 670 C1493 700 1758 527.5 1758 557.5 149true181242339M998 625 C936 668 854 723 796 764 C796 794 796 944 798 995 149false18trueM 735.5 642.0096189432334 L 743 655 L 750.5 642.0096189432334false1242340M798 995 C798 965 748 754 748 724 149true18trueM 342.94685504416486 39.26155629629604 L 328 38 L 334.38088772118584 51.575134323078345false1242341M998 625 C998 655 998 810 998 840 149false18trueM 970.5 582.0096189432334 L 978 595 L 985.5 582.0096189432334false1242342M998 840 C998 810 1060 786 1060 756 149true18trueM 531.9468550441649 114.26155629629604 L 517 113 L 523.3808877211858 126.57513432307834false1242343M998 910 C926 940 860 970 798 995 149false18trueM 830.9903810567666 682.5 L 818 690 L 830.9903810567666 697.5false1242344M873 1030 C903 1030 838 940 868 940 149true18trueM 572.9468550441649 306.261556296296 L 558 305 L 564.3808877211858 318.5751343230783false1242345M1193 835 C1193 865 1193 885 1193 915 149false18trueM 1215.5 659.5096189432334 L 1223 672.5 L 1230.5 659.5096189432334false1242346M1193 915 C1193 885 1218 952.5 1218 922.5 149true18trueM 765.9468550441649 321.261556296296 L 751 320 L 757.3808877211858 333.5751343230783false1242347M1193 985 C1193 1015 1193 1035 1193 1065 149false18trueM 1215.5 862.0096189432334 L 1223 875 L 1230.5 862.0096189432334false1242348M1193 1065 C1193 1035 1218 1142.5 1218 1112.5 149true18trueM 743.9468550441649 427.261556296296 L 729 426 L 735.3808877211858 439.5751343230783false1242349M1193 1135 C1193 1165 1193 1185 1193 1215 149false18trueM 1215.5 1014.5096189432334 L 1223 1027.5 L 1230.5 1014.5096189432334false1242350M1193 1215 C1193 1185 1218 1307.5 1218 1277.5 149true18trueM 730.9468550441649 505.261556296296 L 716 504 L 722.3808877211858 517.5751343230784false1242351M1793 830 C1793 860 1792 994 1793 1015 148false18falsetrueM 1658 652.5 L 1673 652.5 L 1688 652.51242352M1793 1015 C1793 985 1668 932.5 1668 902.5 148true18falsetrueM 922.565967322979 230.6864219732177 L 914 243 L 905.434032677021 255.31357802678231242353M1793 830 C1729 846 1442 914 1398 928 C1399 947 1398 1595 1398 1615 149false18trueM 1665.5 632.0096189432334 L 1673 645 L 1680.5 632.0096189432334false1242354M1398 1615 C1398 1585 1668 925 1668 895 149true18trueM 1066.9468550441647 343.261556296296 L 1052 342 L 1058.380887721186 355.5751343230783false1242355M1398 1685 C1398 1715 1398 1730 1398 1760 148false18falsetrueM 1663 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1403 C578 1402 2263 1409 2294 1409 93false61749.06.0120700M545 1506 C565 1506 2265 1502 2301 1502 93false61756.04.0120701M127 224 C127 174 177 124 227 124 C863 124 1690 124 2326 124 C2376 124 2426 174 2426 224 C2426 831 2426 1621 2426 2228 C2426 2278 2376 2328 2326 2328 C1690 2328 863 2328 227 2328 C177 2328 127 2278 127 2228 C127 1621 127 831 127 224 1true62299.02204.010152115Nucleus Outer Membrane5881365201.01.01601510152215Nucleus Inner Membrane5831470201.01.016015101523235Transcription10901861191.01.020015101524235Proliferation and Survival6901866191.01.020015101525235Survival18881861191.01.020015101526235Protein Synthesis14881294201.01.02001510152715PI3K/Akt Pathway1728667201.31.31601510152815MAPK/ERK Pathway1157667201.31.316015101529235Proliferation14841866191.01.020015101530235Cytosol244162201.61.62001510153115JAK-STAT Pathway584668201.31.31601587220815As Nilotinib is still under clinical trials there is no defined way in literature of routes administration. It is most likely administered intravenously into the blood so it can travel to the bone marrow. 1363155202.22.21601587220915Nilotinib specifically binds and inhibits the BCR/ABL1 fusion protein tyrosine kinase. The BCR-ABL1 is an abnormal enzyme created by the Philadelphia chromosomal translocation. This chromosomal translocation is associated with chronic myeloid leukemia .803215201.91.91601587221015Inhibition of BCR/ABL1 inhibits the JAK-STAT, MAPK/ERK, and PI3K/Akt pathways cascade effects.1618485201.61.61601587221115Decreased signalling of the JAK-STAT pathway decreases the cell's likelihood for proliferation and survival. 6132002202.22.21601587221215Both the JAK-STAT pathway and the MAPK/ERK pathway influence the cell's transcription. Inhibiting these pathways decreases transcription so the cell will eventually die. 10081997192.22.21601587221315The PI3K/AKT pathway is responsible for many regulatory functions of the cell and it's inhibition would affect downstream processes of protein synthesis and cellular proliferation. 14031997202.22.21601587221415With decreased protein synthesis, less cellular functions will be able to proceed eventually killing the cell.18031997202.22.21601557338386109254413752301200239#FFF9C941757627