Molecule Information

General Information of the Molecule (ID: Mol01013)

• Name: Multidrug resistance protein 1 (ABCB1) ,Plasmodium vivax
• Synonyms: MDR1; Multidrug resistant protein 1; Fragment
• Molecule Type: Protein
• Gene Name: MDR1
• Sequence:
  DEVEKELNKKGTFELYKKIKTQKIPFFLPFKCLPSSHRKLLGVSFVCATISGGTLPFFVS
  VFGVIMKNMNLGENVNDIIFSLVLIGIFQFILSFISSFCMDVVTTKILKTLKIEFLKSVF
  YQDGQFHDNNPGSKLTSDLDFYLEQVNAGIGTKFITIFTYASAFLGLYIWSLFKNARLTL
  CITCVFPLIYICGVICNKKVKINKKTSLLYNNNTMSIIEEALVGIRTVVSYCGENTILKK
  FNLSEKLYSKYTLKANLMESLHIGMINGFILASYAFGFWYGTRIIISDLSNQQPNNDFHG
  GSVISILLGVLISMFMLTIILPNITEYMKSLEATNNLYEIINRKPLVENNQDGKKLKDIK
  KIQFKNVRFHYDTRKDVEIYKDLNFTLTEGKTYAFVGESGCGKSTILKLIERLYDPTEGD
  VIINDSHNLKDVNLKWWRSKIGVVSQDPLLFSNSIKNNIKYSLYSLKDLEALSEESNEDG
  FSSQSDSNSRNSCRAKCAGDLNDMIQTTDSTELIQVRKNYETIEDSEVVSVSKKVLIHDF
  VSALPDKYETLVGSNASKLSGGQKQRISIARAIIRNPKILILDEATSSLDNKSEYLVQKT
  INNLKGNENRITIIIAHRLSTIRYANTIFVLSNRENGSTVDVDVLGEDPTKDSNEKNEKH
  DKQEKGGKNSSANQKIGNAGSYIIEQGTHDALMKNKNGIYYTMINNQKVSSKSSSNNDND
  KDSDMKSSIYKDSERGYDPDEANGNAKNESASAKKSEKMSDAKASNTNAGGRLAFLRNLF
  KRKPKAPNNLRVVYREIFSYKKDIAIIALSIMVAGGLYPLFALFYAKYVGTLFDFANLEA
  NSNKYSLYILVIAIAMFISETLKNYYNNVIGEKVEKTMKLRLFENILYQEISFFDQDSHA
  PGLLSAHINRDVHLLKTGLVNNIVIFTHFIVLFLVSMVMSFYFCPIVAAVLTGTYFIFMR
  VFAIRARIAANKDVEKKRVNQPGTAFVYNSDDEIFKDPSFLIQEAFYNMNTVIIYGLEDY
  FCTLIEKAIDYSNKGQKRKTLINSMLWGFSQSAQLFINSFAYWFGSFLIRRGTIQVDDFM
  KSLFTFLFTGSYAGKLMSLKGDSENAKLSFERYYPLITRKSLIDVRDNGGIKIKNSNDIK
  GKIEIMDVNFRYLSRPNVPIYKDLTFSCESKKTTAIVGETGSGKSTVMSLLMRFYDLKND
  HHIVFKNEQTGESSKEQMQQGDEEQNVGMKNANEFSSSKEGADGQSSTLFKNSGKILLDG
  VDICDYNLKDLRNLFSIVSQEPMLFNMSIYENIKFGKENATREDVKRACKFAAIDEFIES
  LPNQYDTNVGPYGKSLSGGQKQRIAIARALLREPKILLLDEATSSLDSNSEKLIEKTIVD
  IKDKADKTIITIAHRIASIKRSDKIVVFNNPDRTGSFVQAQ
• Uniprot ID: A0A1V0PL80_PLAVI

Kingdom: N.A.
Phylum: Apicomplexa
Class: Aconoidasida
Order: Haemosporida
Family: Plasmodiidae
Genus: Plasmodium
Species: Plasmodium vivax

Type(s) of Resistant Mechanism of This Molecule

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Chloroquine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Malaria [ICD-11: 1F45.0] [2]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Chloroquine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium vivax strains; 5855
• Mechanism Description: Patients with CQ-resistant P. vivax parasites presented a higher gene expression of pvcrt-o and pvmdr-1 at D0 and DR when compared to the susceptible group. For the CQR patients, median gene expression values at D0 and DR, presented 2.4 fold (95% CI: 0.96-7.1) and 6.1 fold (95% CI: 3.8-14.3) increase in pvcrt-o levels compared to the susceptible patients at D0 with 0.12 fold (95% CI: 0.034-0.324). Median gene expression for pvmdr-1 presented 2.0 fold (95% CI: 0.95-3.8) and 2.4 fold (95% CI: 0.53-9.1) increase levels at D0 and DR, for the CQR patients versus 0.288 fold (95% CI: 0.068-0.497) for the susceptible patients.

Disease Class: Malaria [ICD-11: 1F45.0] [3]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Chloroquine
• Molecule Alteration: Missense mutation; p.976F
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium vivax isolates; 5855
• Mechanism Description: In Southeast Asia the pvmdr1 976 F allele has been associated with reduced susceptibility to CQ. Finding the pvmdr1 976 F allele in 7/41 (17%) P. vivax might thus indicate a degree of CQ tolerance but probably not resistance in Honduras.

Quinine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Malaria [ICD-11: 1F45.0] [4]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Quinine
• Molecule Alteration: Missense mutation; p.M908L
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium vivax isolates; 5855
• Experiment for Molecule Alteration: In vitro drug assay
• Experiment for Drug Resistance: Analysis of genetic polymorphisms assay
• Mechanism Description: The pvmdr1 M908L substitutions in pvmdr1 in our samples was associated with reduced sensitivity to chloroquine, mefloquine, pyronaridine, piperaquine, quinine, artesunate and dihydroartem.

Clinical Trial Drug(s) 2 drug(s) in total

Tanespimycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: bcr-abl1/leukemia [ICD-11: 2A61] [1]

• Resistant Disease: bcr-abl1/leukemia [ICD-11: 2A61]
• Resistant Drug: Tanespimycin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Drug Resistance: Colony forming unit assay
• Mechanism Description: Chronic long-term exposure to the clinically advanced HSP90i PU-H71 (Zelavespib) led to copy number gain and mutation (p.S164F) of the HSP90AA1 gene, and HSP90 overexpression. In contrast, acquired resistance toward other tested HSP90i (Tanespimycin and Coumermycin A1) was attained by MDR1 efflux pump overexpression. Remarkably, combined CDK7 and HSP90 inhibition display synergistic activity against therapy-resistant BCR-ABL1+ patient leukemia cells via blocking pro-survival HSR and HSP90 overexpression, providing a novel strategy to avoid the emergence of resistance against treatment with HSP90i alone.

BI-847325

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Thyroid gland cancer [ICD-11: 2D10.0] [5]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Sensitive Drug: BI-847325
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Apoptosis assay
• Mechanism Description: Suppression of MAPK signaling pathway activity by BI-847325 treatment could significantly decrease the expression of?MDR1?and?MRP1?genes in C643 and SW1736 ATC cell lines. BI-847325 decreased multidrug resistance through downregulation of MDR1 and MRP1.

Investigative Drug(s) 1 drug(s) in total

Dihydroartemisinin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Malaria [ICD-11: 1F45.0] [4]

• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Resistant Drug: Dihydroartemisinin
• Molecule Alteration: Missense mutation; p.M908L
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium vivax isolates; 5855
• Experiment for Drug Resistance: In vitro drug assay
• Mechanism Description: Studies of genetic polymorphisms in two candidate genes of drug resistance (pvmdr1 and pvcrt-o) of the P. vivax isolates from this area and found association between the M908L substitution in pvmdr1 with reduced sensitivities to and chloroquine, mefloquine, pyronaridine, piperaquine, quinine, artesunate and dihydroartem.

References

• Ref 1: Co-targeting HSP90 alpha and CDK7 overcomes resistance against HSP90 inhibitors in BCR-ABL1+ leukemia cells. Cell Death Dis. 2023 Dec 6;14(12):799.
• Ref 2: Expression levels of pvcrt-o and pvmdr-1 are associated with chloroquine resistance and severe Plasmodium vivax malaria in patients of the Brazilian Amazon. PLoS One. 2014 Aug 26;9(8):e105922. doi: 10.1371/journal.pone.0105922. eCollection 2014.
• Ref 3: Drug resistance associated genetic polymorphisms in Plasmodium falciparum and Plasmodium vivax collected in Honduras, Central America. Malar J. 2011 Dec 19;10:376. doi: 10.1186/1475-2875-10-376.
• Ref 4: Ex vivo susceptibilities of Plasmodium vivax isolates from the China-Myanmar border to antimalarial drugs and association with polymorphisms in Pvmdr1 and Pvcrt-o genes. PLoS Negl Trop Dis. 2020 Jun 12;14(6):e0008255. doi: 10.1371/journal.pntd.0008255. eCollection 2020 Jun.
• Ref 5: BI-847325, a selective dual MEK and Aurora kinases inhibitor, reduces aggressive behavior of anaplastic thyroid carcinoma on an in vitro three-dimensional culture. Cancer Cell Int. 2022 Dec 8;22(1):388.