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G-Protein-Coupled Receptor (GPCR)

GPCRs as the Biggest Drug Target

Pie chartsSubgroups and development statuses of GPCRs

G-protein-coupled receptors (GPCRs) comprise the largest class of membrane receptors and amount to approximately 800 in the human genome (left pie chart). Many of them are crucial in biology and medicine. ~200 of GPCRs respond to endogenous mediators and regulate a wide range of physiological parameters from blood pressure and blood glucose levels to cognitive functions. ~500 are sensory receptors sensing smells, tastes, and other modalities of stimulation. The remaining 100 are orphan, i.e., their ligands are yet to be identified.

Although receptors for endogenous mediators are the most promising group of GPCRs in drug development, only a fraction of them have drugs to target them (right pie chart). Furthermore, recent studies have shown quite a few orphan receptors and sensory receptors to play vital roles in a variety of pathophysiology. Altogether, there remain enormous untapped opportunities with the vast majority of GPCRs.

Nat Rev Drug Discov 2017;16:829-842

GPCRs ranked by the number of targeting drugs
Drug Browser. GPCRdb.

Drugs have been developed for only a small part of GPCRs. The chart above ranks GPCRs in the ascending order according to the number of targeting drugs (the more drugs a GPCR has, the lower it sits). For example, DRD2 at the bottom has more than 80 approved drugs and compounds under R&D, but as you go up, the number of drugs per receptor drops quickly. The top 100 GPCRs keep almost all GPCR drugs to themselves, and the remaining hundreds are left out with no drugs.

Dozens of tractable GPCRs (low-hanging fruits) are well exploited, whereas other GPCRs (high-hanging fruits) are underexploited.

Barriers to GPCR Drug Discovery

One of the barriers to GPCR drug discovery is lack of satisfactory assays.
  • Binding assays are unreliable with many false-positives and false-negatives when it comes to GPCRs
  • No functional assay is adequate.
    • Only a small number of GPCRs are readily amenable to reporter gene assays, and G12/13- and Gi/o-coupled receptors are notoriously intractable.
    • Other functional assays cost a lot of time, work, and/or money. e.g., Western blotting

Breakthrough in GPCR Drug Discovery

To overcome the barriers of GPCR drug discovery and promote drug development, we have innovated a high-performance functional assay. Our assay

  • works for all receptors coupled with any of the major Gα proteins including Gq, Gs, Gi/o, and G12/13
  • is higher in sensitivity and S/B ratio than any existing methods,
  • is low in cost and high in throughput, and
  • makes orphan receptors practical targets.

Our GPCR Functional Assay Platform

A variety of GPCR functional assay methods are available, such as Ca2+ assay, cAMP assay, β-arrestin assay, and reporter gene assay. However, some are clumsy, costly, and time-consuming, and others work with only some GPCRs. There has been no silver bullet … until now. Our proprietary assay platform has overcome limitations of existing methods and made all GPCRs accessible for drug discovery.

Key Features

  • Remarkable sensitivity and S/B ratio
  • An exhaustive library of 313 human GPCRs
  • Works for all receptors coupled with any major Gα proteins incliding Gq, Gs, Gi/o, and G12/13
  • Screens for agonists, antagonists, reverse agonists, PAM, and NAM
  • Low in cost and high in throughput
    • Single cell line for all assays; no need to maintain hundreds of receptor stably expressing cell lines
    • Receptors transiently transfected on microplates
    • No special equipment or reagent required

Core Technology for GPCR functional assay

The core technology for our cell-based GPCR functional assay consists of sensitive and versatile test cells, a Gα protein cocktail, and an exhaustive human GPCR library.

Test cells

Outstandingly sensitive, specific, and versatile

  • Equipped with an artificial gene circuit to specifically amplify GPCR-induced intracellular signals
  • Works for all major Gα proteins including Gq, Gs, Gi/o, and G12/13
  • Verified with 99.1% (216 out of 218) of non-orphan GPCRs
  • Also works with other membrane receptors such as receptor tyrosine kinases
  • International patent filed and exclusively licensed from the University of Tokyo to Tanso Biosciences

Gα protein cocktail

This one-fits-all Gα protein cocktail complements our test cells and enables functional assay for any GPCR under a single protocol even without knowledege of the Gα protein the target receptor is coupled with.

Comprehensive human GPCR library

Industry-leading collection of 313 human GPCRs including 218 non-sensory receptors and 95 orphan receptors. Use of native sequences minimizes signal artifacts.

List

Our human GPCR library

SymbolNomenclatureFamily
GPR55GPR55Cannabinoid receptors
GPR119GPR119Cannabinoid receptors
CNR1CB1 receptorCannabinoid receptors
CNR2CB2 receptorCannabinoid receptors
GPR84GPR84Free fatty acid receptors
GPR120FFA4 receptorFree fatty acid receptors
GPR40FFA1 receptorFree fatty acid receptors
GPR41FFA3 receptorFree fatty acid receptors
GPR43FFA2 receptorFree fatty acid receptors
GABBR1GABAB1GABAB receptors
GABBR2GABAB2GABAB receptors
GPR109AHCA2 receptorHydroxycarboxylic acid receptors
GPR109BHCA3 receptorHydroxycarboxylic acid receptors
GPR81HCA1 receptorHydroxycarboxylic acid receptors
LTB4RBLT1 receptorLeukotriene receptors
LTB4R2BLT2 receptorLeukotriene receptors
CYSLTR1CysLT1 receptorLeukotriene receptors
CYSLTR2CysLT2 receptorLeukotriene receptors
OXER1(GPR170)OXE receptorLeukotriene receptors
PTAFRPAF receptorPlatelet-activating factor receptor
LPAR5LPA5 receptorLysophospholipid (LPA) receptors
LPAR6LPA6 receptorLysophospholipid (LPA) receptors
LPAR1LPA1 receptorLysophospholipid (LPA) receptors
LPAR2LPA2 receptorLysophospholipid (LPA) receptors
LPAR3LPA3 receptorLysophospholipid (LPA) receptors
S1PR1S1P1 receptorLysophospholipid (S1P) receptors
S1PR2S1P2 receptorLysophospholipid (S1P) receptors
S1PR3S1P3 receptorLysophospholipid (S1P) receptors
S1PR4S1P4 receptorLysophospholipid (S1P) receptors
S1PR5S1P5 receptorLysophospholipid (S1P) receptors
LPAR4LPA4 receptorLysophospholipid (LPA) receptors
GRM1mGlu1 receptorMetabotropic glutamate receptors
GRM2mGlu2 receptorMetabotropic glutamate receptors
GRM3mGlu3 receptorMetabotropic glutamate receptors
GRM4mGlu4 receptorMetabotropic glutamate receptors
GRM5mGlu5 receptorMetabotropic glutamate receptors
GRM6mGlu6 receptorMetabotropic glutamate receptors
GRM7mGlu7 receptorMetabotropic glutamate receptors
GRM8mGlu8 receptorMetabotropic glutamate receptors
HTR1A5-HT1A receptor5-Hydroxytryptamine receptors
HTR5A5-HT5A receptor5-Hydroxytryptamine receptors
HTR65-HT6 receptor5-Hydroxytryptamine receptors
CHRM1M1 receptorAcetylcholine receptors (muscarinic)
CHRM2M2 receptorAcetylcholine receptors (muscarinic)
CHRM3M3 receptorAcetylcholine receptors (muscarinic)
CHRM4M4 receptorAcetylcholine receptors (muscarinic)
CHRM5M5 receptorAcetylcholine receptors (muscarinic)
ADORA1A1 receptorAdenosine receptors
ADORA2AA2A receptorAdenosine receptors
HTR1B5-HT1B receptor5-Hydroxytryptamine receptors
ADORA2BA2B receptorAdenosine receptors
DRD1D1 receptorDopamine receptors
DRD2D2 receptorDopamine receptors
DRD3D3 receptorDopamine receptors
DRD4D4 receptorDopamine receptors
DRD5D5 receptorDopamine receptors
ADRA1Bα1B-adrenoceptorAdrenoceptors
ADRA1Dα1D-adrenoceptorAdrenoceptors
ADRA2Aα2A-adrenoceptorAdrenoceptors
ADRA2Bα2B-adrenoceptorAdrenoceptors
HRH1H1 receptorHistamine receptors
HRH3H3 receptorHistamine receptors
ADRA2Cα2C-adrenoceptorAdrenoceptors
ADRB1β1-adrenoceptorAdrenoceptors
MTNR1AMT1 receptorMelatonin receptors
MTNR1BMT2 receptorMelatonin receptors
ADRB2β2-adrenoceptorAdrenoceptors
HTR1D5-HT1D receptor5-Hydroxytryptamine receptors
ADRB3β3-adrenoceptorAdrenoceptors
HTR1E5-ht1e receptor5-Hydroxytryptamine receptors
HTR1F5-HT1F receptor5-Hydroxytryptamine receptors
HTR2B5-HT2B receptor5-Hydroxytryptamine receptors
HTR2C5-HT2C receptor5-Hydroxytryptamine receptors
ADORA3A3 receptorAdenosine receptors
ADRA1Aα1A-adrenoceptorAdrenoceptors
HRH2H2 receptorHistamine receptors
HRH4H4 receptorHistamine receptors
HTR2A5-HT2A receptor5-Hydroxytryptamine receptors
HTR45-HT4 receptor5-Hydroxytryptamine receptors
HTR75-HT7 receptor5-Hydroxytryptamine receptors
GPR34GPR34Orphan receptors
GPR35GPR35Orphan receptors
GPR37GPR37Orphan receptors
GPR37L1GPR37L1Orphan receptors
GPR39GPR39Orphan receptors
GPR45GPR45Orphan receptors
GPR50GPR50Orphan receptors
GPR52GPR52Orphan receptors
GPR61GPR61Orphan receptors
GPR62GPR62Orphan receptors
GPR63GPR63Orphan receptors
GPR65GPR65Orphan receptors
GPR68GPR68Orphan receptors
GPR75GPR75Orphan receptors
GPR78GPR78Orphan receptors
GPR82GPR82Orphan receptors
GPR83GPR83Orphan receptors
GPR85GPR85Orphan receptors
GPR87GPR87Orphan receptors
GPR88GPR88Orphan receptors
GPR101GPR101Orphan receptors
GPR132(G2A)GPR132Orphan receptors
GPR135GPR135Orphan receptors
GPR139GPR139Orphan receptors
GPR141GPR141Orphan receptors
GPR142GPR142Orphan receptors
GPR146GPR146Orphan receptors
GPR148GPR148Orphan receptors
GPR149GPR149Orphan receptors
GPR150GPR150Orphan receptors
GPR151(GALR4)GPR151Orphan receptors
GPR152GPR152Orphan receptors
GPR153GPR153Orphan receptors
GPR160GPR160Orphan receptors
GPR161GPR161Orphan receptors
GPR162GPR162Orphan receptors
GPR171GPR171Orphan receptors
GPR173GPR173Orphan receptors
GPR174GPR174Orphan receptors
GPR182GPR182Orphan receptors
LGR4LGR4Orphan receptors
LGR5LGR5Orphan receptors
LGR6LGR6Orphan receptors
MAS1LMAS1LOrphan receptors
MRGPRDMRGPRDOrphan receptors
MRGPREMRGPREOrphan receptors
MRGPRFMRGPRFOrphan receptors
MRGPRGMRGPRGOrphan receptors
MRGPRX1MRGPRX1Orphan receptors
MRGPRX2MRGPRX2Orphan receptors
MRGPRX3MRGPRX3Orphan receptors
MRGPRX4MRGPRX4Orphan receptors
TAAR2TAAR2Orphan receptors
TAAR5TAAR5Orphan receptors
TAAR6TAAR6Orphan receptors
TAAR8TAAR8Orphan receptors
TAAR9TAAR9Orphan receptors
GPR143GPR143Orphan receptors
GPR157GPR157Orphan receptors
GPR156GPR156Orphan receptors
GPR158GPR158Orphan receptors
GPR30GPEROrphan receptors
GPRC5AGPRC5AOrphan receptors
GPRC5BGPRC5BOrphan receptors
GPRC5CGPRC5COrphan receptors
GPRC5DGPRC5DOrphan receptors
ACKR2(CCBP2)ACKR2Orphan receptors
ACKR4(CCR11)ACKR4Orphan receptors
ACKR1(CCBP1)ACKR1Orphan receptors
AGTR2AT2 receptorOrphan receptors
GPRC6AGPRC6 receptorOrphan receptors
GPR176GPR176Orphan receptors
GPR107GPR107Orphan receptors
GPR137GPR137Orphan receptors
GPR175TPRA1Orphan receptors
CCRL2CCRL2Orphan receptors
ACKR3(CXCR7)ACKR3Orphan receptors
GPR1chemerin receptor 2Orphan receptors
GPR3GPR3Orphan receptors
GPR4GPR4Orphan receptors
GPR6GPR6Orphan receptors
GPR12GPR12Orphan receptors
GPR15GPR15Orphan receptors
GPR17GPR17Orphan receptors
GPR18GPR18Orphan receptors
GPR19GPR19Orphan receptors
GPR20GPR20Orphan receptors
GPR21GPR21Orphan receptors
GPR22GPR22Orphan receptors
GPR25GPR25Orphan receptors
GPR26GPR26Orphan receptors
GPR27GPR27Orphan receptors
GPR31GPR31Orphan receptors
GPR32GPR32Orphan receptors
MAS1LMAS1LOrphan receptors
OXGR1(GPR80/99)oxoglutarate receptorOxoglutarate receptors
P2RY8P2RY8P2Y receptors
P2RY10P2RY10P2Y receptors
P2RY1P2Y1 receptorP2Y receptors
P2RY2P2Y2 receptorP2Y receptors
P2RY4P2Y4 receptorP2Y receptors
P2RY6P2Y6 receptorP2Y receptors
P2RY11P2Y11 receptorP2Y receptors
P2RY12P2Y12 receptorP2Y receptors
P2RY13P2Y13 receptorP2Y receptors
P2RY14P2Y14 receptorP2Y receptors
EDNRAETA receptorEndothelin receptors
EDNRBETB receptorEndothelin receptors
FPR1FPR1Formylpeptide receptors
FPR2FPR2/ALXFormylpeptide receptors
FPR3FPR3Formylpeptide receptors
GALR1GAL1 receptorGalanin receptors
GALR2GAL2 receptorGalanin receptors
GALR3GAL3 receptorGalanin receptors
GHSRghrelin receptorGhrelin receptor
FSHRFSH receptorGlycoprotein hormone receptors
LHCGRLH receptorGlycoprotein hormone receptors
TSHRTSH receptorGlycoprotein hormone receptors
GNRHRGnRH1 receptorGonadotrophin-releasing hormone receptors
KISS1Rkisspeptin receptorKisspeptin receptor
MCHR1MCH1 receptorMelanin-concentrating hormone receptors
MCHR2MCH2 receptorMelanin-concentrating hormone receptors
MC1RMC1 receptorMelanocortin receptors
MC2RMC2 receptorMelanocortin receptors
MC3RMC3 receptorMelanocortin receptors
MC4RMC4 receptorMelanocortin receptors
MC5RMC5 receptorMelanocortin receptors
MLNRmotilin receptorMotilin receptor
NMUR1NMU1 receptorNeuromedin U receptors
NMUR2NMU2 receptorNeuromedin U receptors
NPFFR1NPFF1 receptorNeuropeptide FF/neuropeptide AF receptors
NPFFR2NPFF2 receptorNeuropeptide FF/neuropeptide AF receptors
NPSR1NPS receptorNeuropeptide S receptor
NPBWR1NPBW1 receptorNeuropeptide W/neuropeptide B receptors
NPBWR2NPBW2 receptorNeuropeptide W/neuropeptide B receptors
NPY1RY1 receptorNeuropeptide Y receptors
NPY2RY2 receptorNeuropeptide Y receptors
NPY4RY4 receptorNeuropeptide Y receptors
NPY5RY5 receptorNeuropeptide Y receptors
NTSR1NTS1 receptorNeurotensin receptors
C3AR1C3a receptorComplement peptide receptors
NTSR2NTS2 receptorNeurotensin receptors
OPRD1δ receptorOpioid receptors
OPRK1κ receptorOpioid receptors
OPRM1μ receptorOpioid receptors
C5AR1C5a1 receptorComplement peptide receptors
OPRL1NOP receptorOpioid receptors
HCRTR1OX1 receptorOrexin receptors
HCRTR2OX2 receptorOrexin receptors
C5AR2C5a2 receptorComplement peptide receptors
QRFPRQRFP receptorQRFP receptor
PROKR1PKR1Prokineticin receptors
PROKR2PKR2Prokineticin receptors
PRLHRPrRP receptorProlactin-releasing peptide receptor
AGTR1AT1 receptorAngiotensin receptors
F2RPAR1Proteinase-activated receptors
F2RL1PAR2Proteinase-activated receptors
F2RL2PAR3Proteinase-activated receptors
F2RL3PAR4Proteinase-activated receptors
RXFP1RXFP1Relaxin family peptide receptors
RXFP2RXFP2Relaxin family peptide receptors
RXFP3RXFP3Relaxin family peptide receptors
RXFP4RXFP4Relaxin family peptide receptors
SSTR1SST1 receptorSomatostatin receptors
SSTR2SST2 receptorSomatostatin receptors
SSTR3SST3 receptorSomatostatin receptors
SSTR4SST4 receptorSomatostatin receptors
SSTR5SST5 receptorSomatostatin receptors
APLNRapelin receptorApelin receptor
TACR1NK1 receptorTachykinin receptors
TACR2NK2 receptorTachykinin receptors
TACR3NK3 receptorTachykinin receptors
TRHRTRH1 receptorThyrotropin-releasing hormone receptors
UTS2RUT receptorUrotensin receptor
AVPR1AV1A receptorVasopressin and oxytocin receptors
AVPR1BV1B receptorVasopressin and oxytocin receptors
AVPR2V2 receptorVasopressin and oxytocin receptors
OXTROT receptorVasopressin and oxytocin receptors
NMBRBB1 receptorBombesin receptors
GRPRBB2 receptorBombesin receptors
BRS3BB3 receptorBombesin receptors
BDKRB1B1 receptorBradykinin receptors
BDKRB2B2 receptorBradykinin receptors
CCR1CCR1Chemokine receptors
CCR2CCR2Chemokine receptors
CCR3CCR3Chemokine receptors
CCR4CCR4Chemokine receptors
CCR5CCR5Chemokine receptors
CCR6CCR6Chemokine receptors
CCR7CCR7Chemokine receptors
CCR8CCR8Chemokine receptors
CCR9CCR9Chemokine receptors
CCR10CCR10Chemokine receptors
CXCR1CXCR1Chemokine receptors
CXCR2CXCR2Chemokine receptors
CXCR3CXCR3Chemokine receptors
CXCR4CXCR4Chemokine receptors
CXCR5CXCR5Chemokine receptors
CXCR6CXCR6Chemokine receptors
CX3CR1CX3CR1Chemokine receptors
XCR1XCR1Chemokine receptors
CCKARCCK1 receptorCholecystokinin receptors
CCKBRCCK2 receptorCholecystokinin receptors
CMKLR1chemerin receptor 1Chemerin receptors
CRHR1CRF1 receptorCorticotropin-releasing factor receptors
CRHR2CRF2 receptorCorticotropin-releasing factor receptors
GHRHRGHRH receptorGlucagon receptor family
GIPRGIP receptorGlucagon receptor family
GLP1RGLP-1 receptorGlucagon receptor family
GLP2RGLP-2 receptorGlucagon receptor family
GCGRglucagon receptorGlucagon receptor family
SCTRsecretin receptorGlucagon receptor family
PTH1RPTH1 receptorParathyroid hormone receptors
PTH2RPTH2 receptorParathyroid hormone receptors
ADCYAP1R1PAC1 receptorVIP and PACAP receptors
VIPR1VPAC1 receptorVIP and PACAP receptors
VIPR2VPAC2 receptorVIP and PACAP receptors
CALCRCT receptorCalcitonin receptors
CALCRLcalcitonin receptor-like receptorCalcitonin receptors
CASRCaS receptorCalcium-sensing receptor
PTGDRDP1 receptorProstanoid receptors
PTGDR2DP2 receptorProstanoid receptors
PTGER1EP1 receptorProstanoid receptors
PTGER2EP2 receptorProstanoid receptors
PTGER3EP3 receptorProstanoid receptors
PTGER4EP4 receptorProstanoid receptors
PTGFRFP receptorProstanoid receptors
PTGIRIP receptorProstanoid receptors
TBXA2RTP receptorProstanoid receptors
GPBAR1(TGR5)GPBA receptorBile acid receptor
GPR183GPR183Steroid receptors
GPR91succinate receptorSuccinate receptor
TAAR1TA1 receptorTrace amine receptor

Validation of Our Assay Method

Our assay has yielded consistent readouts with results from existing methods and at high sensitivity and S/B ratio.

AGTR1, a peptide-ligand receptor

In our assay, AGTR1 responded to its agonist at high sensitivity and S/B ratio and consistently with the results from existing methods.

Our method

Tanso Biosciences' assay

Existing methods

Binding assay

Nature. 1991;351:233-6.
LigandKi (nM) ± s.e.m.n
Sar1-angiotensin II0.38 ± 0.073
Sar1, Ala8-angiotensin II0.43 ± 0.083
Sar1, Ile8-angiotensin II0.46 ± 0.033
Ile7-angiotensin III1.1 ± 0.33
Angiotensin II1.6 ± 0.23
Angiotensin III5.4 ± 0.53
Dup7536.3 ± 0.93
Angiotensin I74 ± 123
Arg8-vasopressin>1,0002
Endothelin>1,0002
PD123177>10,0002
Competition binding profile of COS-7/Ba23.i401 membranes. Ki (nM) values were derived from the relationship Ki = IC50 ± (F/Kd). IC50 values were determined using the nonlinear regression, single-site competition curve-fitting function of Graphpad lnplot. F is the concentration in nM of radioligand added in each experiment and Kd is the affinity constant of [125I]sarile (0.68 nM) derived from saturation binding assays.

Inositol phosphate formation

J Biol Chem. 1995;270:28511-4. Inositol phosphate formation

Inositol phosphate formation by transfected wild-type AT1 receptor and the D281A mutant. Inositol phosphate formed in response to [Sar1] Ang II, [ Sar1,Gln2] Ang II and the non-peptide agonist, L-162,313, in COS 1 cells transfected with wild-type and the D281A mutant. The affinity constant (Ki) of wild-type and mutant D281A receptors, respectively, for [Sar1] Ang II is 0.32 nM and 83.2 nM, for [ Sar1,Gln2] Ang II is 52.7 nM and 304 nM, and for L-162,313 is 56.2 nM and 50.4 nM.

GPR91: a low molecular ligand receptor

In our assay, GPR91 responded to its agonist at high sensitivity and S/B ratio and consistently with the results from existing methods.

Our method

Tanso's method

Existing method

Ca2+ assay

Nature. 2004;429:188-93. Calcium assay

Flt3: a receptor tyrosine kinase (RTK)

Our method proved to also work for other membrane receptors than GPCRs.

Our method

Cells from the same line of test cells were used in this assay as in assays for GPCRs, and Flt3 was transiently transfected into cells in the same way as GPCRs.

Tanso Biosciences' assay was sensitive to Flt3 activation

Existing method

Cell proliferation

Retrieved from R&D Systems' website
Dose-dependent cell proliferation of Flt-3 expressing cells

Frequently Asked Questions

  • Do your test cells amplify noise as well as signals?
  • The artificial gene circuit in our cells is designed to amplify signals quadratically while boosting noise only by ~two-fold. The cells have responded to stimuli with >100-fold signal/background ratios and small standard errors in many GPCRs(see Validation).
  • Can your test cells examine biased agonism?
  • No, you need in vivo experiments, not cell-based assay, to test if compounds act in a biased way since biased agonism is defined by the expression pattern of Gα proteins in the target tissue.
  • Can your test cells be sub-licensed?
  • No, we do not sub-license our cells for now.
  • Are your test cells capable of expressing orphan GPCRs in the plasma membrane when they are transfected?
  • It is essential to make sure that introduced orphan GPCRs are present in the plasma membrane all the more because they do not have agonists to prove that pharmacologically. We are testing each orphan receptor now.
  • Do you have animal GPCR panels?
  • We are expanding our library to mouse and rat GPCRs. If you are interested in a particular receptor, we can prioritize cloning it and will be ready to assay it in a few weeks.

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