Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT7WZIJ)

• DTT Name: CAAX farnesyltransferase beta (FNTB)
• Synonyms: RAS proteins prenyltransferasebeta; FTase-beta; FNTB; CAAX farnesyltransferase beta subunit
• Gene Name: FNTB
• DTT Type: Literature-reported target; [1]
• BioChemical Class: Alkyl aryl transferase
• UniProt ID: FNTB_HUMAN
• TTD ID: T86428
• EC Number: EC 2.5.1.58
• Sequence:
  MASPSSFTYYCPPSSSPVWSEPLYSLRPEHARERLQDDSVETVTSIEQAKVEEKIQEVFS
  SYKFNHLVPRLVLQREKHFHYLKRGLRQLTDAYECLDASRPWLCYWILHSLELLDEPIPQ
  IVATDVCQFLELCQSPEGGFGGGPGQYPHLAPTYAAVNALCIIGTEEAYDIINREKLLQY
  LYSLKQPDGSFLMHVGGEVDVRSAYCAASVASLTNIITPDLFEGTAEWIARCQNWEGGIG
  GVPGMEAHGGYTFCGLAALVILKRERSLNLKSLLQWVTSRQMRFEGGFQGRCNKLVDGCY
  SFWQAGLLPLLHRALHAQGDPALSMSHWMFHQQALQEYILMCCQCPAGGLLDKPGKSRDF
  YHTCYCLSGLSIAQHFGSGAMLHDVVLGVPENALQPTHPVYNIGPDKVIQATTYFLQKPV
  PGFEELKDETSAEPATD
• Function: Essential subunit of the farnesyltransferase complex. Catalyzes the transfer of a farnesyl moiety from farnesyl diphosphate to a cysteine at the fourth position from the C- terminus of several proteins having the C-terminal sequence Cys- aliphatic-aliphatic-X.
• KEGG Pathway:
  Terpenoid backbone biosynthesis (hsa00900)
  Biosynthesis of antibiotics (hsa01130)
• Reactome Pathway: Inactivation, recovery and regulation of the phototransduction cascade (R-HSA-2514859)

Molecular Interaction Atlas (MIA) of This DTT

17 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ABT-100	DMPFLS5	Solid tumour/cancer	2A00-2F9Z	Terminated	[2]
ABT-839	DM4UN9A	Non-small-cell lung cancer	2C25.Y	Terminated	[3]
B-956	DM1IO9X	Solid tumour/cancer	2A00-2F9Z	Terminated	[4]
BMS-182566	DMO7C09	Solid tumour/cancer	2A00-2F9Z	Terminated	[1]
BMS-185857	DMTA7O8	Solid tumour/cancer	2A00-2F9Z	Terminated	[1]
CP-663427	DMIZMJD	Solid tumour/cancer	2A00-2F9Z	Terminated	[5]
FUSIDIENOL	DMI1Y92	N. A.	N. A.	Terminated	[6]
L-731735	DM1XBKC	Solid tumour/cancer	2A00-2F9Z	Terminated	[7]
L-739749	DMAUG0L	Solid tumour/cancer	2A00-2F9Z	Terminated	[7]
L-745631	DM4UP7R	Solid tumour/cancer	2A00-2F9Z	Terminated	[7]
MANUMYCIN A	DM1SWOY	N. A.	N. A.	Terminated	[8]
RPR-113829	DMJ63GW	N. A.	N. A.	Terminated	[9]
RPR-114334	DMAIJT6	N. A.	N. A.	Terminated	[9]
Sch-207758	DM037SB	Solid tumour/cancer	2A00-2F9Z	Terminated	[10]
SCH-44342	DMUL4VX	N. A.	N. A.	Terminated	[7]
XR-3005	DMJLRC7	Colorectal cancer	2B91.Z	Terminated	[1]
XR-3054	DMXI39O	Solid tumour/cancer	2A00-2F9Z	Terminated	[11]

22 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(Z)-2-Methyl-3-tetradecyl-but-2-enedioic acid	DM18R6J	Discovery agent	N.A.	Investigative	[7]
A-313326	DML4P6O	Discovery agent	N.A.	Investigative	[3]
ACTINOPLANIC ACID A	DMXIDS9	Discovery agent	N.A.	Investigative	[7]
ALPHA-HYDROXYFARNESYLPHOSPHONIC ACID	DMIH38V	Discovery agent	N.A.	Investigative	[12]
Arteminolide	DM8SP4X	Discovery agent	N.A.	Investigative	[6]
BMS-316810	DM21CYI	Discovery agent	N.A.	Investigative	[13]
BMS-404683	DM1ZDFG	Discovery agent	N.A.	Investigative	[14]
CLAVARINONE	DMIX347	Discovery agent	N.A.	Investigative	[15]
CYLINDROL A	DMCRU4H	Discovery agent	N.A.	Investigative	[7]
F-12458	DMXHKE3	Solid tumour/cancer	2A00-2F9Z	Investigative	[16]
FARNESYL	DMXYWD7	Discovery agent	N.A.	Investigative	[12]
FTI 276	DMN2Q7Y	Discovery agent	N.A.	Investigative	[17]
GERANYLGERANYL DIPHOSPHATE	DMJZ0AM	Discovery agent	N.A.	Investigative	[12]
H-SMGLPCVVM-OH	DMA91T4	Discovery agent	N.A.	Investigative	[18]
L-739750	DMAHC9Z	Discovery agent	N.A.	Investigative	[7]
LB42908	DM6RH19	Discovery agent	N.A.	Investigative	[19]
PB-27	DMZURA2	Discovery agent	N.A.	Investigative	[14]
PB-80	DMAOIW5	Discovery agent	N.A.	Investigative	[14]
PB-81	DM9V807	Discovery agent	N.A.	Investigative	[14]
PD-83176	DMSIMKZ	Discovery agent	N.A.	Investigative	[20]
Prenyl pyrophosphate analogue	DM9HSQJ	Discovery agent	N.A.	Investigative	[21]
PREUSSOMERIN	DM5P1NZ	Discovery agent	N.A.	Investigative	[7]

References

• [1] US patent application no. 2005,0227,929, Combination therapy comprising a cox-2 inhibitor and an antineoplastic agent.
• [2] Potent farnesyltransferase inhibitor ABT-100 abrogates acute allograft rejection. J Heart Lung Transplant. 2005 Sep;24(9):1403-9.
• [3] Design and synthesis of o-trifluoromethylbiphenyl substituted 2-amino-nicotinonitriles as inhibitors of farnesyltransferase. Bioorg Med Chem Lett. 2005 Jan 3;15(1):153-8.
• [4] Inhibition of human tumor xenograft growth by treatment with the farnesyl transferase inhibitor B956. Cancer Res. 1995 Nov 15;55(22):5310-4.
• [5] WO patent application no. 2011,0881,26, Treatment of viral infection with prenyltransferase inhibitors.
• [6] Modeling of binding modes and inhibition mechanism of some natural ligands of farnesyl transferase using molecular docking. J Med Chem. 2002 Mar 28;45(7):1460-5.
• [7] Ras farnesyltransferase: a new therapeutic target. J Med Chem. 1997 Sep 12;40(19):2971-90.
• [8] A novel metal-chelating inhibitor of protein farnesyltransferase. Bioorg Med Chem Lett. 2003 May 5;13(9):1523-6.
• [9] Novel conformationally extended naphthalene-based inhibitors of farnesyltransferase. J Med Chem. 1997 Jun 6;40(12):1763-7.
• [10] Exploring the role of bromine at C(10) of (+)-4-[2-[4-(8-chloro-3,10-dibromo- 6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(R)-yl)-1-piperidinyl]-2- oxoethyl]-1-piperidinecarboxamide (Sch-66336): the discovery of indolocycloheptapyridine inhibitors of farnesyl protein transferase. J Med Chem. 2002 Aug 29;45(18):3854-64.
• [11] XR3054, structurally related to limonene, is a novel inhibitor of farnesyl protein transferase. Eur J Cancer. 1999 Jun;35(6):1014-9.
• [12] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [13] Design, synthesis, and structure-activity relationships of tetrahydroquinoline-based farnesyltransferase inhibitors. Bioorg Med Chem Lett. 2005 Apr 1;15(7):1895-9.
• [14] Protein farnesyltransferase inhibitors exhibit potent antimalarial activity. J Med Chem. 2005 Jun 2;48(11):3704-13.
• [15] Clavaric acid and steroidal analogues as Ras- and FPP-directed inhibitors of human farnesyl-protein transferase. J Med Chem. 1998 Nov 5;41(23):4492-501.
• [16] Recent progress in protein farnesyltransferase inhibition. IDrugs. 2000 Nov;3(11):1336-45.
• [17] Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by inducing cytoplasmic accumulation of inactive Ras-Raf complexes. J Biol Chem. 1995 Nov 10;270(45):26802-6.
• [18] Improvement of biological activity and proteolytic stability of peptides by coupling with a cyclic peptide. Bioorg Med Chem Lett. 2003 Aug 4;13(15):2583-6.
• [19] A novel class of highly potent, selective, and non-peptidic inhibitor of Ras farnesyltransferase (FTase). Bioorg Med Chem Lett. 2001 Dec 3;11(23):3069-72.
• [20] Structure-activity relationships of cysteine-lacking pentapeptide derivatives that inhibit ras farnesyltransferase. J Med Chem. 1997 Jan 17;40(2):192-200.
• [21] Synthesis and evaluation of benzophenone-based photoaffinity labeling analogs of prenyl pyrophosphates containing stable amide linkages, Bioorg. Med. Chem. Lett. 7(16):2125-2130 (1997).