Target Information
| Target General Information | Top | |||||
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| Target ID |
T93062
(Former ID: TTDC00030)
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| Target Name |
Multidrug resistance protein 3 (ABCB4)
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| Synonyms |
PGY3; MDR3; ATP-binding cassette sub-family B member 4; ABCB4
Click to Show/Hide
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| Gene Name |
ABCB4
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Breast cancer [ICD-11: 2C60-2C6Y] | |||||
| Function |
Mediates ATP-dependent export of organic anions and drugs from the cytoplasm. Hydrolyzes ATP with low efficiency. Not capable of conferring drug resistance. Mediates the translocation of phosphatidylcholine across the canalicular membrane of the hepatocyte.
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| BioChemical Class |
Acid anhydrides hydrolase
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| UniProt ID | ||||||
| EC Number |
EC 7.6.2.1
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| Sequence |
MDLEAAKNGTAWRPTSAEGDFELGISSKQKRKKTKTVKMIGVLTLFRYSDWQDKLFMSLG
TIMAIAHGSGLPLMMIVFGEMTDKFVDTAGNFSFPVNFSLSLLNPGKILEEEMTRYAYYY SGLGAGVLVAAYIQVSFWTLAAGRQIRKIRQKFFHAILRQEIGWFDINDTTELNTRLTDD ISKISEGIGDKVGMFFQAVATFFAGFIVGFIRGWKLTLVIMAISPILGLSAAVWAKILSA FSDKELAAYAKAGAVAEEALGAIRTVIAFGGQNKELERYQKHLENAKEIGIKKAISANIS MGIAFLLIYASYALAFWYGSTLVISKEYTIGNAMTVFFSILIGAFSVGQAAPCIDAFANA RGAAYVIFDIIDNNPKIDSFSERGHKPDSIKGNLEFNDVHFSYPSRANVKILKGLNLKVQ SGQTVALVGSSGCGKSTTVQLIQRLYDPDEGTINIDGQDIRNFNVNYLREIIGVVSQEPV LFSTTIAENICYGRGNVTMDEIKKAVKEANAYEFIMKLPQKFDTLVGERGAQLSGGQKQR IAIARALVRNPKILLLDEATSALDTESEAEVQAALDKAREGRTTIVIAHRLSTVRNADVI AGFEDGVIVEQGSHSELMKKEGVYFKLVNMQTSGSQIQSEEFELNDEKAATRMAPNGWKS RLFRHSTQKNLKNSQMCQKSLDVETDGLEANVPPVSFLKVLKLNKTEWPYFVVGTVCAIA NGGLQPAFSVIFSEIIAIFGPGDDAVKQQKCNIFSLIFLFLGIISFFTFFLQGFTFGKAG EILTRRLRSMAFKAMLRQDMSWFDDHKNSTGALSTRLATDAAQVQGATGTRLALIAQNIA NLGTGIIISFIYGWQLTLLLLAVVPIIAVSGIVEMKLLAGNAKRDKKELEAAGKIATEAI ENIRTVVSLTQERKFESMYVEKLYGPYRNSVQKAHIYGITFSISQAFMYFSYAGCFRFGA YLIVNGHMRFRDVILVFSAIVFGAVALGHASSFAPDYAKAKLSAAHLFMLFERQPLIDSY SEEGLKPDKFEGNITFNEVVFNYPTRANVPVLQGLSLEVKKGQTLALVGSSGCGKSTVVQ LLERFYDPLAGTVFVDFGFQLLDGQEAKKLNVQWLRAQLGIVSQEPILFDCSIAENIAYG DNSRVVSQDEIVSAAKAANIHPFIETLPHKYETRVGDKGTQLSGGQKQRIAIARALIRQP QILLLDEATSALDTESEKVVQEALDKAREGRTCIVIAHRLSTIQNADLIVVFQNGRVKEH GTHQQLLAQKGIYFSMVSVQAGTQNL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T08THQ | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | Encequidar | Drug Info | Phase 2 | Metastatic breast cancer | [2] | |
| Discontinued Drug(s) | [+] 4 Discontinued Drugs | + | ||||
| 1 | Dofequidar fumarate | Drug Info | Discontinued in Phase 3 | Solid tumour/cancer | [1] | |
| 2 | LY335979 | Drug Info | Discontinued in Phase 3 | Acute myeloid leukaemia | [3] | |
| 3 | Dexniguldipine | Drug Info | Discontinued in Phase 2 | Solid tumour/cancer | [4], [5] | |
| 4 | LANIQUIDAR | Drug Info | Discontinued in Phase 2 | Solid tumour/cancer | [6] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | Encequidar | Drug Info | [7] | |||
| Modulator | [+] 4 Modulator drugs | + | ||||
| 1 | Dofequidar fumarate | Drug Info | [1] | |||
| 2 | LY335979 | Drug Info | [8] | |||
| 3 | Dexniguldipine | Drug Info | [9] | |||
| 4 | LANIQUIDAR | Drug Info | [10] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Adenosine triphosphate | Ligand Info | |||||
| Structure Description | Nucleotide bound ABCB4 | PDB:6S7P | ||||
| Method | Electron microscopy | Resolution | 3.20 Å | Mutation | Yes | [11] |
| PDB Sequence |
VLTLFRYSDW
51 QDKLFMSLGT61 IMAIAHGSGL71 PLMMIVFGEM81 TDKPGKILEE111 EMTRYAYYYS 121 GLGAGVLVAA131 YIQVSFWTLA141 AGRQIRKIRQ151 KFFHAILRQE161 IGWFDINDTT 171 ELNTRLTDDI181 SKISEGIGDK191 VGMFFQAVAT201 FFAGFIVGFI211 RGWKLTLVIM 221 AISPILGLSA231 AVWAKILSAF241 SDKELAAYAK251 AGAVAEEALG261 AIRTVIAFGG 271 QNKELERYQK281 HLENAKEIGI291 KKAISANISM301 GIAFLLIYAS311 YALAFWYGST 321 LVISKEYTIG331 NAMTVFFSIL341 IGAFSVGQAA351 PCIDAFANAR361 GAAYVIFDII 371 DNNPKIDSFS381 ERGHKPDSIK391 GNLEFNDVHF401 SYPSRANVKI411 LKGLNLKVQS 421 GQTVALVGSS431 GCGKSTTVQL441 IQRLYDPDEG451 TINIDGQDIR461 NFNVNYLREI 471 IGVVSQEPVL481 FSTTIAENIC491 YGRGNVTMDE501 IKKAVKEANA511 YEFIMKLPQK 521 FDTLVGERGA531 QLSGGQKQRI541 AIARALVRNP551 KILLLDQATS561 ALDTESEAEV 571 QAALDKAREG581 RTTIVIAHRL591 STVRNADVIA601 GFEDGVIVEQ611 GSHSELMKKE 621 GVYFKLVNVP693 PVSFLKVLKL703 NKTEWPYFVV713 GTVCAIANGG723 LQPAFSVIFS 733 EIIAIFGPGD743 DAVKQQKCNI753 FSLIFLFLGI763 ISFFTFFLQG773 FTFGKAGEIL 783 TRRLRSMAFK793 AMLRQDMSWF803 DDHKNSTGAL813 STRLATDAAQ823 VQGATGTRLA 833 LIAQNIANLG843 TGIIISFIYG853 WQLTLLLLAV863 VPIIAVSGIV873 EMKLLAGNAK 883 RDKKELEAAG893 KIATEAIENI903 RTVVSLTQER913 KFESMYVEKL923 YGPYRNSVQK 933 AHIYGITFSI943 SQAFMYFSYA953 GCFRFGAYLI963 VNGHMRFRDV973 ILVFSAIVFG 983 AVALGHASSF993 APDYAKAKLS1003 AAHLFMLFER1013 QPLIDSYSEE1023 GLKPDKFEGN 1033 ITFNEVVFNY1043 PTRANVPVLQ1053 GLSLEVKKGQ1063 TLALVGSSGC1073 GKSTVVQLLE 1083 RFYDPLAGTV1093 LLDGQEAKKL1103 NVQWLRAQLG1113 IVSQEPILFD1123 CSIAENIAYG 1133 DNSRVVSQDE1143 IVSAAKAANI1153 HPFIETLPHK1163 YETRVGDKGT1173 QLSGGQKQRI 1183 AIARALIRQP1193 QILLLDQATS1203 ALDTESEKVV1213 QEALDKAREG1223 RTCIVIAHRL 1233 STIQNADLIV1243 VFQNGRVK
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ASP166
3.995
ARG264
4.078
TYR403
3.555
SER405
3.167
ARG406
2.770
ILE411
3.371
SER430
4.113
SER431
4.094
GLY432
3.100
CYS433
3.379
GLY434
3.225
LYS435
2.881
SER436
2.492
THR437
3.141
TYR446
4.209
GLN477
2.513
ALA531
3.546
GLN532
3.711
LEU533
4.154
SER534
3.279
GLY535
3.400
GLY536
3.069
GLN537
3.495
ASP557
3.347
ALA562
4.250
ILE587
4.641
ASP804
3.831
ARG904
3.847
TYR1043
3.571
THR1045
3.203
ARG1046
2.991
VAL1051
4.219
SER1070
4.226
SER1071
2.820
GLY1072
3.280
CYS1073
3.427
GLY1074
3.496
LYS1075
2.347
SER1076
3.068
THR1077
3.230
TYR1086
4.364
GLN1117
2.583
PHE1156
3.630
THR1173
3.334
GLN1174
3.684
LEU1175
4.191
SER1176
3.246
GLY1177
3.077
GLY1178
4.369
GLN1179
3.308
GLN1200
4.845
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| Ligand Name: Posaconazole | Ligand Info | |||||
| Structure Description | Nanodisc reconstituted human ABCB4 in complex with 4B1-Fab (posaconazole-bound, inward-open conformation) | PDB:7NIW | ||||
| Method | Electron microscopy | Resolution | 3.80 Å | Mutation | Yes | [12] |
| PDB Sequence |
TLFRYSDWQD
53 KLFMSLGTIM63 AIAHGSGLPL73 MMIVFGEMTD83 KFVDTAGNFS93 FPVPGKILEE 111 EMTRYAYYYS121 GLGAGVLVAA131 YIQVSFWTLA141 AGRQIRKIRQ151 KFFHAILRQE 161 IGWFDINDTT171 ELNTRLTDDI181 SKISEGIGDK191 VGMFFQAVAT201 FFAGFIVGFI 211 RGWKLTLVIM221 AISPILGLSA231 AVWAKILSAF241 SDKELAAYAK251 AGAVAEEALG 261 AIRTVIAFGG271 QNKELERYQK281 HLENAKEIGI291 KKAISANISM301 GIAFLLIYAS 311 YALAFWYGST321 LVISKEYTIG331 NAMTVFFSIL341 IGAFSVGQAA351 PCIDAFANAR 361 GAAYVIFDII371 DNNPKIDSFS381 ERGHKPDSIK391 GNLEFNDVHF401 SYPSRANVKI 411 LKGLNLKVQS421 GQTVALVGSS431 GCGKSTTVQL441 IQRLYDPDEG451 TINIDGQDIR 461 NFNVNYLREI471 IGVVSQEPVL481 FSTTIAENIC491 YGRGNVTMDE501 IKKAVKEANA 511 YEFIMKLPQK521 FDTLVGERGA531 QLSGGQKQRI541 AIARALVRNP551 KILLLDQATS 561 ALDTESEAEV571 QAALDKAREG581 RTTIVIAHRL591 STVRNADVIA601 GFEDGVIVEQ 611 GSHSELMKKE621 GVYFKLVNAN691 VPPVSFLKVL701 KLNKTEWPYF711 VVGTVCAIAN 721 GGLQPAFSVI731 FSEIIAIFGP741 GDDAVKQQKC751 NIFSLIFLFL761 GIISFFTFFL 771 QGFTFGKAGE781 ILTRRLRSMA791 FKAMLRQDMS801 WFDDHKNSTG811 ALSTRLATDA 821 AQVQGATGTR831 LALIAQNIAN841 LGTGIIISFI851 YGWQLTLLLL861 AVVPIIAVSG 871 IVEMKLLAGN881 AKRDKKELEA891 AGKIATEAIE901 NIRTVVSLTQ911 ERKFESMYVE 921 KLYGPYRNSV931 QKAHIYGITF941 SISQAFMYFS951 YAGCFRFGAY961 LIVNGHMRFR 971 DVILVFSAIV981 FGAVALGHAS991 SFAPDYAKAK1001 LSAAHLFMLF1011 ERQPLIDSYS 1021 EEGLKPDKFE1031 GNITFNEVVF1041 NYPTRANVPV1051 LQGLSLEVKK1061 GQTLALVGSS 1071 GCGKSTVVQL1081 LERFYDPLAG1091 TVLLDGQEAK1101 KLNVQWLRAQ1111 LGIVSQEPIL 1121 FDCSIAENIA1131 YGDNSRVVSQ1141 DEIVSAAKAA1151 NIHPFIETLP1161 HKYETRVGDK 1171 GTQLSGGQKQ1181 RIAIARALIR1191 QPQILLLDQA1201 TSALDTESEK1211 VVQEALDKAR 1221 EGRTCIVIAH1231 RLSTIQNADL1241 IVVFQNGRVK1251
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LEU71
4.155
MET75
2.911
ASN298
4.335
MET301
3.402
PHE305
4.728
PHE338
4.418
LEU341
3.349
ILE342
3.335
PHE345
3.109
SER346
4.867
GLN349
4.872
ASN721
4.424
GLN725
3.772
PHE769
3.250
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| ABC transporters | hsa02010 | Affiliated Target |
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| Class: Environmental Information Processing => Membrane transport | Pathway Hierarchy | ||
| Bile secretion | hsa04976 | Affiliated Target |
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| Class: Organismal Systems => Digestive system | Pathway Hierarchy | ||
| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | ABC transporters | |||||
| 2 | Bile secretion | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | PPARA activates gene expression | |||||
| 2 | ABC-family proteins mediated transport | |||||
| WikiPathways | [+] 3 WikiPathways | + | ||||
| 1 | Nuclear Receptors in Lipid Metabolism and Toxicity | |||||
| 2 | Farnesoid X Receptor Pathway | |||||
| 3 | Regulation of Lipid Metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha) | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Reversal of multidrug resistance by a novel quinoline derivative, MS-209. Cancer Chemother Pharmacol. 1995;35(4):271-7. | |||||
| REF 2 | ClinicalTrials.gov (NCT01042379) I-SPY TRIAL: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer (I-SPY). U.S. National Institutes of Health. | |||||
| REF 3 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005159) | |||||
| REF 4 | URL: 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: 463). | |||||
| REF 5 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002528) | |||||
| REF 6 | ClinicalTrials.gov (NCT00028873) R101933 Combined With Chemotherapy in Treating Patients With Metastatic Breast Cancer That Has Not Responded to Previous Chemotherapy. U.S. National Institutes of Health. | |||||
| REF 7 | Discovery of Encequidar, First-in-Class Intestine Specific P-glycoprotein Inhibitor. J Med Chem. 2021 Apr 8;64(7):3677-3693. | |||||
| REF 8 | A Phase I trial of a potent P-glycoprotein inhibitor, zosuquidar trihydrochloride (LY335979), administered intravenously in combination with doxoru... Clin Cancer Res. 2004 May 15;10(10):3265-72. | |||||
| REF 9 | Mechanism of action of dexniguldipine-HCl (B8509-035), a new potent modulator of multidrug resistance. Biochem Pharmacol. 1995 Mar 1;49(5):603-9. | |||||
| REF 10 | Evaluation of [11C]laniquidar as a tracer of P-glycoprotein: radiosynthesis and biodistribution in rats. Nucl Med Biol. 2009 Aug;36(6):643-9. | |||||
| REF 11 | Structure of the human lipid exporter ABCB4 in a lipid environment. Nat Struct Mol Biol. 2020 Jan;27(1):62-70. | |||||
| REF 12 | Structures of ABCB4 provide insight into phosphatidylcholine translocation. Proc Natl Acad Sci U S A. 2021 Aug 17;118(33):e2106702118. | |||||
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