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ABCB1

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Target id: 768

Nomenclature: ABCB1

Abbreviated Name: MDR1, PGP1

Systematic Nomenclature: ABCB1

Family: ABCB subfamily

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 12 1280 7q21.12 ABCB1 ATP binding cassette subfamily B member 1
Mouse 12 1276 5 3.43 cM Abcb1a ATP-binding cassette, sub-family B (MDR/TAP), member 1A
Rat - - Abcb1a ATP binding cassette subfamily B member 1A
Previous and Unofficial Names Click here for help
P-glycoprotein 1 | ABC20 | CD243 | CLCS | GP170 | MDR1 | PGY1 | colchicin sensitivity | multidrug resistance protein 1 | Abcb1 | ATP-binding cassette, sub-family B (MDR/TAP), member 1 | ATP-binding cassette, subfamily B (MDR/TAP), member 1A | Mdr1a | multiple drug resistant 1a | Evi32 | MDR3 | mdr-3 | Pgp | Pgy3 | Pgy-3 | P-gp | Abcb1a | ATP binding cassette subfamily B member 1 | ATP-binding cassette
Database Links Click here for help
Alphafold
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Molecular structure of human P-glycoprotein (ABCB1) in the ATP-bound, outward-facing conformation
PDB Id:  6C0V
Ligand:  ATP   This ligand is endogenous
Resolution:  3.4Å
Species:  Human
References:  3

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
zosuquidar Small molecule or natural product Hs Inhibition 7.2 pKi 2
pKi 7.2 (Ki 5.9x10-8 M) [2]
valspodar Peptide Hs Inhibition 5.9 pKi 10
pKi 5.9 (Ki 1.3x10-6 M) [10]
WS-898 Small molecule or natural product Hs Inhibition 8.3 pIC50 9
pIC50 8.3 (IC50 5x10-9 M) [9]
tariquidar Small molecule or natural product Ligand has a PDB structure Mm Inhibition 7.4 pIC50 5
pIC50 7.4 (IC50 3.8x10-8 M) [5]
Description: Measuring the effect of XR9576 on accumulation of [3H] daunorubicin in the multidrug resistant mouse mammary carcinoma cell line EMT6/AR1.0
compound 14 [PMID: 30925062] Small molecule or natural product Click here for species-specific activity table Hs Competitive 5.8 – 6.2 pIC50 7
pIC50 6.2 (IC50 6.76x10-7 M) [7]
Description: Measuring inhibition of cyclosporine A transport in A2780/ADR cells expressing hABCB1.
pIC50 5.8 (IC50 1.73x10-6 M) [7]
Description: Measuring inhibition of calcein AM transport in A2780/ADR cells expressing hABCB1.
biricodar Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.3 pIC50 8
pIC50 5.3 (IC50 5x10-6 M) [8]
View species-specific inhibitor tables
Inhibitor Comments
Laniquidar (R101933) is a third generation P-gp inhibitor that reached phase 2 clinical evaluation.
Biologically Significant Variant Comments
Nonsense mutation in ABCB1 has been described in collie dogs [4,6] and when these animals are treated with ivermectin they develop potentially fatal neurologic disorders, due to a toxic accumulation of ivermectin in the central nervous system. Similar ivermectin-induced pathology has been noted in humans. In 2020 mutated human ABCB1 alleles were identified in a patient who developed serious ivermectin toxicity following a single oral dose of the drug. Genetic analysis revealed that this patient harboured a different nonsense alteration in each copy of their ABCB1 genes. Both mutations generated premature stop codons and truncated transporter proteins that lacked the C-terminal nucleotide-binding domain, rendering the proteins incapable of drug-transport [1].

References

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1. Baudou E, Lespine A, Durrieu G, André F, Gandia P, Durand C, Cunat S. (2020) Serious Ivermectin Toxicity and Human ABCB1 Nonsense Mutations. N Engl J Med, 383: 787-789 [Epub ahead of print]. DOI: 10.1056/NEJMc1917344

2. Dantzig AH, Shepard RL, Law KL, Tabas L, Pratt S, Gillespie JS, Binkley SN, Kuhfeld MT, Starling JJ, Wrighton SA. (1999) Selectivity of the multidrug resistance modulator, LY335979, for P-glycoprotein and effect on cytochrome P-450 activities. J Pharmacol Exp Ther, 290 (2): 854-62. [PMID:10411602]

3. Kim Y, Chen J. (2018) Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation. Science, 359 (6378): 915-919. [PMID:29371429]

4. Mealey KL. (2004) Therapeutic implications of the MDR-1 gene. J Vet Pharmacol Ther, 27 (5): 257-64. [PMID:15500562]

5. Roe M, Folkes A, Ashworth P, Brumwell J, Chima L, Hunjan S, Pretswell I, Dangerfield W, Ryder H, Charlton P. (1999) Reversal of P-glycoprotein mediated multidrug resistance by novel anthranilamide derivatives. Bioorg Med Chem Lett, 9 (4): 595-600. [PMID:10098671]

6. Schinkel AH, Smit JJ, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, Mol CA, van der Valk MA, Robanus-Maandag EC, te Riele HP et al.. (1994) Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell, 77 (4): 491-502. [PMID:7910522]

7. Silbermann K, Stefan SM, Elshawadfy R, Namasivayam V, Wiese M. (2019) Identification of Thienopyrimidine Scaffold as an Inhibitor of the ABC Transport Protein ABCC1 (MRP1) and Related Transporters Using a Combined Virtual Screening Approach. J Med Chem, 62 (9): 4383-4400. [PMID:30925062]

8. Wang S, Ryder H, Pretswell I, Depledge P, Milton J, Hancox TC, Dale I, Dangerfield W, Charlton P, Faint R et al.. (2002) Studies on quinazolinones as dual inhibitors of Pgp and MRP1 in multidrug resistance. Bioorg Med Chem Lett, 12 (4): 571-4. [PMID:11844674]

9. Wang S, Wang SQ, Teng QX, Lei ZN, Chen ZS, Chen XB, Liu HM, Yu B. (2021) Discovery of the Triazolo[1,5-a]Pyrimidine-Based Derivative WS-898 as a Highly Efficacious and Orally Bioavailable ABCB1 Inhibitor Capable of Overcoming Multidrug Resistance. J Med Chem, [Epub ahead of print]. DOI: 10.1021/acs.jmedchem.1c01498 [PMID:34723530]

10. Wigler PW. (1999) PSC833, cyclosporin A, and dexniguldipine effects on cellular calcein retention and inhibition of the multidrug resistance pump in human leukemic lymphoblasts. Biochem Biophys Res Commun, 257 (2): 410-3. [PMID:10198227]

Contributors

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