Target Information

Target General Information

Target ID

T74238 (Former ID: TTDI01916)

Target Name

Leukotriene CysLT2 receptor (CYSLTR2)

Synonyms

hGPCR21; PSEC0146; HPN321; Gprotein coupled receptor HG57; Gprotein coupled receptor GPCR21; G-protein coupled receptor HG57; G-protein coupled receptor GPCR21; Cysteinyl leukotriene receptor 2; CysLTR2; CYSLT2R; CYSLT2

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Gene Name

CYSLTR2

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Asthma [ICD-11: CA23]

Function

The response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system. Stimulation by BAY u9773, a partial agonist, induces specific contractions of pulmonary veins and might also have an indirect role in the relaxation of the pulmonary vascular endothelium. The rank order of affinities for the leukotrienes is LTC4 = LTD4 >> LTE4. Receptor for cysteinyl leukotrienes.

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BioChemical Class

GPCR rhodopsin

UniProt ID

CLTR2_HUMAN

Sequence

MERKFMSLQPSISVSEMEPNGTFSNNNSRNCTIENFKREFFPIVYLIIFFWGVLGNGLSI
YVFLQPYKKSTSVNVFMLNLAISDLLFISTLPFRADYYLRGSNWIFGDLACRIMSYSLYV
NMYSSIYFLTVLSVVRFLAMVHPFRLLHVTSIRSAWILCGIIWILIMASSIMLLDSGSEQ
NGSVTSCLELNLYKIAKLQTMNYIALVVGCLLPFFTLSICYLLIIRVLLKVEVPESGLRV
SHRKALTTIIITLIIFFLCFLPYHTLRTVHLTTWKVGLCKDRLHKALVITLALAAANACF
NPLLYYFAGENFKDRLKSALRKGHPQKAKTKCVFPVSVWLRKETRV

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3D Structure

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AlphaFold

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

BAY-X-7195

Drug Info

Phase 2

Asthma

[2]

Discontinued Drug(s)

[+] 6 Discontinued Drugs

AS-35

Drug Info

Discontinued in Phase 2

Asthma

[3]

DS-4574

Drug Info

Discontinued in Phase 2

Asthma

[4]

Sulukast

Drug Info

Discontinued in Phase 2

Asthma

[5], [6]

ICI-198615

Drug Info

Terminated

Asthma

[8], [9]

LY-290154

Drug Info

Terminated

Asthma

[10]

MDL-43291

Drug Info

Terminated

Asthma

[11]

Mode of Action

[+] 3 Modes of Action

Modulator

[+] 7 Modulator drugs

BAY-X-7195

Drug Info

[1]

AS-35

Drug Info

[12], [13]

DS-4574

Drug Info

[14], [15]

Sulukast

Drug Info

[16]

LY-290154

Drug Info

[18]

MDL-43291

Drug Info

[19]

CGP-57698

Drug Info

[22]

Antagonist

[+] 5 Antagonist drugs

ICI-198615

Drug Info

[17]

BayCysLT2

Drug Info

[20]

BAYu9773

Drug Info

[21]

HAMI3379

Drug Info

[23]

pobilukast

Drug Info

[27]

Agonist

[+] 5 Agonist drugs

LTC4

Drug Info

[24]

LTD4

Drug Info

[24], [25]

LTE4

Drug Info

[26]

N-methyl LTC4

Drug Info

[26]

[3H]LTC4

Drug Info

[28]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Human Similarity Proteins Human Pathway Affiliation

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Human Similarity Proteins

Human Pathway Affiliation

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Olfactory receptor 2A2 (OR2A2)	PF13853	21.708 (61/281)	1.06E-04
Olfactory receptor 2S2 (OR2S2)	PF13853	23.301 (72/309)	1.82E-04
Olfactory receptor 2T3 (OR2T3)	PF13853	20.656 (63/305)	1.98E-04
Olfactory receptor 2A14 (OR2A14)	PF13853	22.064 (62/281)	5.37E-04
Olfactory receptor 2W1 (OR2W1)	PF13853	25.163 (77/306)	5.55E-04
Olfactory receptor 1I1 (OR1I1)	PF13853	22.481 (29/129)	1.00E-03
Olfactory receptor 2T6 (OR2T6)	PF13853	22.483 (67/298)	2.00E-03
Olfactory receptor 2M3 (OR2M3)	PF13853	27.049 (33/122)	3.00E-03
Olfactory receptor 2T34 (OR2T34)	PF13853	20.656 (63/305)	3.00E-03
Olfactory receptor 2AG1 (OR2AG1)	PF13853	23.438 (30/128)	4.00E-03
Olfactory receptor 14A16 (OR14A16)	PF13853	28.276 (41/145)	4.00E-03
Olfactory receptor 2AG2 (OR2AG2)	PF13853	23.704 (32/135)	4.00E-03
Olfactory receptor 14J1 (OR14J1)	PF13853	22.876 (70/306)	5.00E-03
Click to Show/Hide the Information of Human Similarity Proteins

KEGG Pathway	Pathway ID	Affiliated Target
Calcium signaling pathway	hsa04020	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Neuroactive ligand-receptor interaction	hsa04080	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 2 KEGG Pathways

Calcium signaling pathway

Neuroactive ligand-receptor interaction

NetPath Pathway

[+] 2 NetPath Pathways

IL4 Signaling Pathway

IL3 Signaling Pathway

PID Pathway

[+] 1 PID Pathways

Endothelins

Reactome

[+] 2 Reactome Pathways

Leukotriene receptors

G alpha (q) signalling events

WikiPathways

[+] 4 WikiPathways

GPCRs, Class A Rhodopsin-like

Gastrin-CREB signalling pathway via PKC and MAPK

GPCR ligand binding

GPCR downstream signaling

References

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REF 1

The effect of a novel leukotriene C4/D4 antagonist, BAY-x-7195, on experimental allergic reactions. Prostaglandins. 1995 Nov-Dec;50(5-6):269-85.

REF 2

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003794)

REF 3

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001439)

REF 4

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000587)

REF 5

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 3327).

REF 6

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000090)

REF 7

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000089)

REF 8

REF 9

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002386)

REF 10

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007201)

REF 11

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000087)

REF 12

Inhibition of radiolabeled leukotriene-binding by AS-35 in guinea pig lung membrane fraction. Jpn J Pharmacol. 1992 Apr;58(4):357-64.

REF 13

Peptide leukotriene antagonistic activity of AS-35, a new antiallergic drug. Jpn J Pharmacol. 1992 Apr;58(4):347-55.

REF 14

Inhibitory effect of DS-4574, a mast cell stabilizer with peptidoleukotriene receptor antagonism, on gastric acid secretion in rats. Eur J Pharmacol. 1994 Apr 1;255(1-3):229-34.

REF 15

Antagonistic action of DS-4574 against leukotrienes in guinea-pig smooth muscle. Arch Int Pharmacodyn Ther. 1991 Nov-Dec;314:147-59.

REF 16

The pharmacological evaluation of LY 170680, a novel leukotriene D4 and E4 antagonist in the guinea-pig. Br J Pharmacol. 1989 Sep;98(1):259-67.

REF 17

Heterogeneity of binding sites for ICI 198,615 in human lung parenchyma. Biochem Pharmacol. 1992 Oct 6;44(7):1411-5.

REF 18

DOI: 10.1021/op060036x

REF 19

Conformationally restricted leukotriene receptor antagonists: [(octahydro-2-oxo-7-tetradecylidene-2H-1-benzopyran-8-yl)thio]ace tic acids. Pharmacology. 1990;40(5):271-6.

REF 20

Synthesis of cysteinyl leukotrienes in human endothelial cells: subcellular localization and autocrine signaling through the CysLT2 receptor. FASEB J. 2011 Oct;25(10):3519-28.

REF 21

BAY u9773, a novel antagonist of cysteinyl-leukotrienes with activity against two receptor subtypes. Eur J Pharmacol. 1994 Nov 3;264(3):317-23.

REF 22

A kinetic binding study to evaluate the pharmacological profile of a specific leukotriene C(4) binding site not coupled to contraction in human lun... Mol Pharmacol. 2000 Jun;57(6):1182-9.

REF 23

Pharmacological characterization of the first potent and selective antagonist at the cysteinyl leukotriene 2 (CysLT(2)) receptor. Br J Pharmacol. 2010 May;160(2):399-409.

REF 24

Molecular cloning and characterization of a second human cysteinyl leukotriene receptor: discovery of a subtype selective agonist. Mol Pharmacol. 2000 Dec;58(6):1601-8.

REF 25

Characterization of the human cysteinyl leukotriene 2 receptor. J Biol Chem. 2000 Sep 29;275(39):30531-6.

REF 26

Differential signaling of cysteinyl leukotrienes and a novel cysteinyl leukotriene receptor 2 (CysLT agonist, N-methyl-leukotriene C in calcium reporter and beta arrestin assays. Mol Pharmacol. 2011 Feb;79(2):270-8.

REF 27

REF 28

The molecular characterization and tissue distribution of the human cysteinyl leukotriene CysLT(2) receptor. Biochem Biophys Res Commun. 2000 Aug 2;274(2):316-22.

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