Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTXQKM3)

• DTT Name: Farnesyl protein transferase (Ftase)
• Synonyms: Ras proteins prenyltransferase; Protein farnesyltransferase; Ftase; CAAX farnesyltransferase
• Gene Name: FNTB
• DTT Type: Successful target; [1]
• BioChemical Class: Alkyl aryl transferase
• UniProt ID: FNTA_HUMAN ; FNTB_HUMAN
• TTD ID: T13127
• Sequence:
  MAATEGVGEAAQGGEPGQPAQPPPQPHPPPPQQQHKEEMAAEAGEAVASPMDDGFVSLDS
  PSYVLYRDRAEWADIDPVPQNDGPNPVVQIIYSDKFRDVYDYFRAVLQRDERSERAFKLT
  RDAIELNAANYTVWHFRRVLLKSLQKDLHEEMNYITAIIEEQPKNYQVWHHRRVLVEWLR
  DPSQELEFIADILNQDAKNYHAWQHRQWVIQEFKLWDNELQYVDQLLKEDVRNNSVWNQR
  YFVISNTTGYNDRAVLEREVQYTLEMIKLVPHNESAWNYLKGILQDRGLSKYPNLLNQLL
  DLQPSHSSPYLIAFLVDIYEDMLENQCDNKEDILNKALELCEILAKEKDTIRKEYWRYIG
  RSLQSKHSTENDSPTNVQQ
• Function: Essential subunit of both the farnesyltransferase and the geranylgeranyltransferase complex. Contributes to the transfer of a farnesyl or geranylgeranyl moiety from farnesyl or geranylgeranyl diphosphate to a cysteine at the fourth position from the C-terminus of several proteins having the C-terminal sequence Cys-aliphatic-aliphatic-X. May positively regulate neuromuscular junction development downstream of MUSK via its function in RAC1prenylation and activation.
• KEGG Pathway:
  Terpenoid backbone biosynthesis (hsa00900)
  Biosynthesis of antibiotics (hsa01130)
• Reactome Pathway:
  Inactivation, recovery and regulation of the phototransduction cascade (R-HSA-2514859)
  Apoptotic cleavage of cellular proteins (R-HSA-111465)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Lonafarnib	DMGM2Z6	Hutchinson-Gilford progeria syndrome	LD2B	Approved	[2]

4 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Zarnestra	DMF30HL	Acute myeloid leukaemia	2A60	Phase 3	[1]
BMS214662	DM5M48F	Non-small-cell lung cancer	2C25.Y	Phase 1	[3]
GGTI-2418	DM8U23L	Solid tumour/cancer	2A00-2F9Z	Phase 1	[4]
L-778123	DMWSC5L	Lymphoma	2A80-2A86	Phase 1	[5]

8 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ABT-839	DM4UN9A	Non-small-cell lung cancer	2C25.Y	Terminated	[6]
AZD3409	DM3WFB5	Solid tumour/cancer	2A00-2F9Z	Terminated	[7]
L-731735	DM1XBKC	Solid tumour/cancer	2A00-2F9Z	Terminated	[8]
L-745631	DM4UP7R	Solid tumour/cancer	2A00-2F9Z	Terminated	[9]
MANUMYCIN A	DM1SWOY	N. A.	N. A.	Terminated	[10]
RPR-113829	DMJ63GW	N. A.	N. A.	Terminated	[11]
RPR-114334	DMAIJT6	N. A.	N. A.	Terminated	[11]
SCH-44342	DMUL4VX	N. A.	N. A.	Terminated	[12]

11 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	[9]
ACTINOPLANIC ACID A	DMXIDS9	Discovery agent	N.A.	Investigative	[9]
ALPHA-HYDROXYFARNESYLPHOSPHONIC ACID	DMIH38V	Discovery agent	N.A.	Investigative	[13]
BMS-404683	DM1ZDFG	Discovery agent	N.A.	Investigative	[14]
CLAVARINONE	DMIX347	Discovery agent	N.A.	Investigative	[15]
FARNESYL	DMXYWD7	Discovery agent	N.A.	Investigative	[13]
GERANYLGERANYL DIPHOSPHATE	DMJZ0AM	Discovery agent	N.A.	Investigative	[13]
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	[16]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rectal cancer	2C82	Rectal colon tissue	5.43E-01	-0.1	-0.4
Lung cancer	2C82	Lung tissue	1.40E-07	-0.22	-0.45
Bladder cancer	2C82	Bladder tissue	1.85E-24	-0.97	-11.86

References

• [1] Tipifarnib in the treatment of newly diagnosed acute myelogenous leukemia. Biologics. 2008 Sep;2(3):491-500.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [3] Farnesyltransferase inhibitor BMS-214662 induces apoptosis in B-cell chronic lymphocytic leukemia cells. Leukemia. 2004 Oct;18(10):1599-604.
• [4] Company report (Prescient)
• [5] Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein trans... Mol Cancer Ther. 2002 Jul;1(9):747-58.
• [6] Aryl tetrahydropyridine inhibitors of farnesyltransferase: glycine, phenylalanine and histidine derivatives. Bioorg Med Chem Lett. 2003 Apr 7;13(7):1359-62.
• [7] AZD3409 inhibits the growth of breast cancer cells with intrinsic resistance to the EGFR tyrosine kinase inhibitor gefitinib. Breast Cancer Res Treat. 2007 May;102(3):275-82.
• [8] N-Arylalkyl pseudopeptide inhibitors of farnesyltransferase. J Med Chem. 1998 Jul 2;41(14):2651-6.
• [9] Ras farnesyltransferase: a new therapeutic target. J Med Chem. 1997 Sep 12;40(19):2971-90.
• [10] A novel metal-chelating inhibitor of protein farnesyltransferase. Bioorg Med Chem Lett. 2003 May 5;13(9):1523-6.
• [11] Novel conformationally extended naphthalene-based inhibitors of farnesyltransferase. J Med Chem. 1997 Jun 6;40(12):1763-7.
• [12] Tricyclic farnesyl protein transferase inhibitors: crystallographic and calorimetric studies of structure-activity relationships. J Med Chem. 1999 Jun 17;42(12):2125-35.
• [13] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [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] Structure-activity relationships of cysteine-lacking pentapeptide derivatives that inhibit ras farnesyltransferase. J Med Chem. 1997 Jan 17;40(2):192-200.