Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTJUXV6)

• DTT Name: Multidrug resistance protein 3 (ABCB4)
• Synonyms: PGY3; P-gp; MDR3; ATP-binding cassette sub-family B member 4; ABCB4
• Gene Name: ABCB4
• DTT Type: Clinical trial target; [1]
• Related Disease: Breast cancer [ICD-11: 2C60-2C6Y]
• BioChemical Class: Acid anhydrides hydrolase
• UniProt ID: MDR3_HUMAN
• TTD ID: T93062
• EC Number: EC 7.6.2.1
• Sequence:
  MDLEAAKNGTAWRPTSAEGDFELGISSKQKRKKTKTVKMIGVLTLFRYSDWQDKLFMSLG
  TIMAIAHGSGLPLMMIVFGEMTDKFVDTAGNFSFPVNFSLSLLNPGKILEEEMTRYAYYY
  SGLGAGVLVAAYIQVSFWTLAAGRQIRKIRQKFFHAILRQEIGWFDINDTTELNTRLTDD
  ISKISEGIGDKVGMFFQAVATFFAGFIVGFIRGWKLTLVIMAISPILGLSAAVWAKILSA
  FSDKELAAYAKAGAVAEEALGAIRTVIAFGGQNKELERYQKHLENAKEIGIKKAISANIS
  MGIAFLLIYASYALAFWYGSTLVISKEYTIGNAMTVFFSILIGAFSVGQAAPCIDAFANA
  RGAAYVIFDIIDNNPKIDSFSERGHKPDSIKGNLEFNDVHFSYPSRANVKILKGLNLKVQ
  SGQTVALVGSSGCGKSTTVQLIQRLYDPDEGTINIDGQDIRNFNVNYLREIIGVVSQEPV
  LFSTTIAENICYGRGNVTMDEIKKAVKEANAYEFIMKLPQKFDTLVGERGAQLSGGQKQR
  IAIARALVRNPKILLLDEATSALDTESEAEVQAALDKAREGRTTIVIAHRLSTVRNADVI
  AGFEDGVIVEQGSHSELMKKEGVYFKLVNMQTSGSQIQSEEFELNDEKAATRMAPNGWKS
  RLFRHSTQKNLKNSQMCQKSLDVETDGLEANVPPVSFLKVLKLNKTEWPYFVVGTVCAIA
  NGGLQPAFSVIFSEIIAIFGPGDDAVKQQKCNIFSLIFLFLGIISFFTFFLQGFTFGKAG
  EILTRRLRSMAFKAMLRQDMSWFDDHKNSTGALSTRLATDAAQVQGATGTRLALIAQNIA
  NLGTGIIISFIYGWQLTLLLLAVVPIIAVSGIVEMKLLAGNAKRDKKELEAAGKIATEAI
  ENIRTVVSLTQERKFESMYVEKLYGPYRNSVQKAHIYGITFSISQAFMYFSYAGCFRFGA
  YLIVNGHMRFRDVILVFSAIVFGAVALGHASSFAPDYAKAKLSAAHLFMLFERQPLIDSY
  SEEGLKPDKFEGNITFNEVVFNYPTRANVPVLQGLSLEVKKGQTLALVGSSGCGKSTVVQ
  LLERFYDPLAGTVFVDFGFQLLDGQEAKKLNVQWLRAQLGIVSQEPILFDCSIAENIAYG
  DNSRVVSQDEIVSAAKAANIHPFIETLPHKYETRVGDKGTQLSGGQKQRIAIARALIRQP
  QILLLDEATSALDTESEKVVQEALDKAREGRTCIVIAHRLSTIQNADLIVVFQNGRVKEH
  GTHQQLLAQKGIYFSMVSVQAGTQNL
• 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.
• Reactome Pathway:
  ABC-family proteins mediated transport (R-HSA-382556)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Encequidar	DMM8Z3Q	Metastatic breast cancer	2C6Y	Phase 2	[2]

4 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Dofequidar fumarate	DMWMHU7	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 3	[1]
LY335979	DM2KITF	Acute myeloid leukaemia	2A60	Discontinued in Phase 3	[3]
Dexniguldipine	DMLZIT2	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 2	[4]
LANIQUIDAR	DM3YABD	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 2	[5]

The Drug Transporter (DTP) Role of This DTT

• DTT DTP Name: Multidrug resistance protein 3 (ABCB4) DTP Info
• Gene Name: ABCB4

5 Approved Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Digoxin	DMQCTIH	Arrhythmia	BC9Z	Approved	[6]
Paclitaxel	DMLB81S	Breast cancer	2C60-2C65	Approved	[6]
Silodosin	DMJSBT6	Benign prostatic hyperplasia	GA90	Approved	[7]
Verapamil	DMA7PEW	Hypertension	BA00-BA04	Approved	[6]
Vinblastine	DM5TVS3	Solid tumour/cancer	2A00-2F9Z	Approved	[6]

References

• [1] Reversal of multidrug resistance by a novel quinoline derivative, MS-209. Cancer Chemother Pharmacol. 1995;35(4):271-7.
• [2] Discovery of Encequidar, First-in-Class Intestine Specific P-glycoprotein Inhibitor. J Med Chem. 2021 Apr 8;64(7):3677-3693.
• [3] 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.
• [4] Mechanism of action of dexniguldipine-HCl (B8509-035), a new potent modulator of multidrug resistance. Biochem Pharmacol. 1995 Mar 1;49(5):603-9.
• [5] Evaluation of [11C]laniquidar as a tracer of P-glycoprotein: radiosynthesis and biodistribution in rats. Nucl Med Biol. 2009 Aug;36(6):643-9.
• [6] MDR3 P-glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping. J Biol Chem. 2000 Aug 4;275(31):23530-9.
• [7] Pharmacokinetics and disposition of silodosin (KMD-3213)]. Yakugaku Zasshi. 2006 Mar;126 Spec no.:237-45.