Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTQ6S1K)

• DTT Name: Lysophosphatidic acid receptor 1 (LPAR1)
• Synonyms: Lysophosphatidic acid receptor Edg-2; LPA1; LPA-1; LPA receptor 1; EDG2; EDG 2 receptor
• Gene Name: LPAR1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: LPAR1_HUMAN
• TTD ID: T92640
• Sequence:
  MAAISTSIPVISQPQFTAMNEPQCFYNESIAFFYNRSGKHLATEWNTVSKLVMGLGITVC
  IFIMLANLLVMVAIYVNRRFHFPIYYLMANLAAADFFAGLAYFYLMFNTGPNTRRLTVST
  WLLRQGLIDTSLTASVANLLAIAIERHITVFRMQLHTRMSNRRVVVVIVVIWTMAIVMGA
  IPSVGWNCICDIENCSNMAPLYSDSYLVFWAIFNLVTFVVMVVLYAHIFGYVRQRTMRMS
  RHSSGPRRNRDTMMSLLKTVVIVLGAFIICWTPGLVLLLLDVCCPQCDVLAYEKFFLLLA
  EFNSAMNPIIYSYRDKEMSATFRQILCCQRSENPTGPTEGSDRSASSLNHTILAGVHSND
  HSVV
• Function: Plays a role in the reorganization of the actin cytoskeleton, cell migration, differentiation and proliferation, and thereby contributes to the responses to tissue damage and infectious agents. Activates downstream signaling cascades via the G(i)/G(o), G(12)/G(13), and G(q) families of heteromeric G proteins. Signaling inhibits adenylyl cyclase activity and decreases cellular cAMP levels. Signaling triggers an increase of cytoplasmic Ca(2+) levels. Activates RALA; this leads to the activation of phospholipase C (PLC) and the formation of inositol 1,4,5-trisphosphate. Signaling mediates activation of down-stream MAP kinases. Contributes to the regulation of cell shape. Promotes Rho-dependent reorganization of the actin cytoskeleton in neuronal cells and neurite retraction. Promotes the activation of Rho and the formation of actin stress fibers. Promotes formation of lamellipodia at the leading edge of migrating cells via activation of RAC1. Through its function as lysophosphatidic acid receptor, plays a role in chemotaxis and cell migration, including responses to injury and wounding. Plays a role in triggering inflammation in response to bacterial lipopolysaccharide (LPS) via its interaction with CD14. Promotes cell proliferation in response to lysophosphatidic acid. Required for normal skeleton development. May play a role in osteoblast differentiation. Required for normal brain development. Required for normal proliferation, survival and maturation of newly formed neurons in the adult dentate gyrus. Plays a role in pain perception and in the initiation of neuropathic pain. Receptor for lysophosphatidic acid (LPA).
• KEGG Pathway:
  Rap1 signaling pathway (hsa04015)
  Neuroactive ligand-receptor interaction (hsa04080)
  PI3K-Akt signaling pathway (hsa04151)
  Gap junction (hsa04540)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Lysosphingolipid and LPA receptors (R-HSA-419408)
  G alpha (q) signalling events (R-HSA-416476)

Molecular Interaction Atlas (MIA) of This DTT

4 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BMS-986020	DMHMV6E	Scleroderma	4A42	Phase 2	[2]
BMS-986278	DMD27RW	Pulmonary fibrosis	CB03.4	Phase 2	[3]
SAR-100842	DMDMQW0	Fibrosis	GA14-GC01	Phase 2	[1]
BMS-986337	DM9GC6L	Pulmonary fibrosis	CB03.4	Phase 1	[4]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BMS-986202	DM8TAI9	Idiopathic pulmonary fibrosis	CB03.4	Preclinical	[5]

32 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(1,1-Difluoro-pentadecyl)-phosphonic acid	DMDK59X	Discovery agent	N.A.	Investigative	[6]
2-oleoyl-LPA	DMN9OS1	Discovery agent	N.A.	Investigative	[7]
alkyl OMPT	DMM19AO	Discovery agent	N.A.	Investigative	[8]
anti-BrP-LPA	DM3IOR0	Discovery agent	N.A.	Investigative	[9]
BrP-LPA	DMPGEO1	Discovery agent	N.A.	Investigative	[9]
Decyl-phosphonic acid	DMFT3J2	Discovery agent	N.A.	Investigative	[6]
dioctanoylglycerol pyrophosphate	DM0QY1V	Discovery agent	N.A.	Investigative	[10]
Dodecyl-phosphonic acid	DMLHKI9	Discovery agent	N.A.	Investigative	[6]
dodecyl-thiophosphate	DMAJVPI	Discovery agent	N.A.	Investigative	[6]
Ki16425	DMJTDK9	Discovery agent	N.A.	Investigative	[11]
LPA	DMI5XR1	Discovery agent	N.A.	Investigative	[12]
NAEPA	DM38XWZ	Discovery agent	N.A.	Investigative	[13]
oleoyl-thiophosphate	DM1TAM9	Discovery agent	N.A.	Investigative	[14]
ONO-3080573	DM8LKED	Discovery agent	N.A.	Investigative	[15]
ONO-9780307	DMATXHR	Discovery agent	N.A.	Investigative	[15]
ONO-9910539	DML4DPV	Discovery agent	N.A.	Investigative	[15]
Phosphoric acid mono-((E)-dec-4-enyl) ester	DMS57HX	Discovery agent	N.A.	Investigative	[6]
Phosphoric acid mono-((E)-dodec-9-enyl) ester	DMC873V	Discovery agent	N.A.	Investigative	[6]
Phosphoric acid mono-((E)-tetradec-11-enyl) ester	DMET9ZC	Discovery agent	N.A.	Investigative	[6]
Phosphoric acid mono-((E)-tetradec-9-enyl) ester	DME8APC	Discovery agent	N.A.	Investigative	[6]
Phosphoric acid monodec-9-enyl ester	DMANVJY	Discovery agent	N.A.	Investigative	[6]
Phosphoric acid monododecyl ester	DMME0VN	Discovery agent	N.A.	Investigative	[6]
Phosphoric acid monotetradecyl ester	DMG5MJL	Discovery agent	N.A.	Investigative	[6]
syn-BrP-LPA	DMM5PVL	Discovery agent	N.A.	Investigative	[9]
T13	DMVRJEL	Discovery agent	N.A.	Investigative	[14]
Tetradecyl-phosphonic acid	DMABITD	Discovery agent	N.A.	Investigative	[6]
Thiophosphoric acid (E)-dodec-9-enyl ester	DMZ4FCB	Discovery agent	N.A.	Investigative	[6]
Thiophosphoric acid (E)-tetradec-9-enyl ester	DMYOXJ4	Discovery agent	N.A.	Investigative	[6]
Thiophosphoric acid dec-9-enyl ester	DM12NGE	Discovery agent	N.A.	Investigative	[6]
Thiophosphoric acid decyl ester	DM36KW9	Discovery agent	N.A.	Investigative	[6]
VPC12249	DM6F0VR	Discovery agent	N.A.	Investigative	[16]
VPC32183	DMLK3I9	Discovery agent	N.A.	Investigative	[17]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Idiopathic pulmonary fibrosis	CA23	Lung tissue	6.48E-01	-0.04	-0.24

References

• [1] Promising Pharmacological Directions in the World of Lysophosphatidic Acid Signaling. Biomol Ther (Seoul) 2015 January; 23(1): 1-11.
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Phase 2 trial design of BMS-986278, a lysophosphatidic acid receptor 1 (LPA(1)) antagonist, in patients with idiopathic pulmonary fibrosis (IPF) or progressive fibrotic interstitial lung disease (PF-ILD). BMJ Open Respir Res. 2021 Dec;8(1):e001026.
• [4] ClinicalTrials.gov (NCT04550195) A Double-Blind, Placebo-Controlled, Randomized, Single and Multiple Ascending Dose Study of the Safety and Tolerability, and Pharmacokinetics (Including Food Effect, pH Effect and Japanese Bridging Study) of BMS-986337 Following Oral Administration in Healthy Participants. U.S.National Institutes of Health.
• [5] Pharmacokinetic and pharmacodynamic characterization of an oral lysophosphatidic acid type 1 receptor-selective antagonist. J Pharmacol Exp Ther. 2011 Mar;336(3):693-700.
• [6] Synthesis, structure-activity relationships, and biological evaluation of fatty alcohol phosphates as lysophosphatidic acid receptor ligands, activ... J Med Chem. 2005 Jul 28;48(15):4919-30.
• [7] Lysophosphatidic acid (LPA) receptors of the EDG family are differentially activated by LPA species. Structure-activity relationship of cloned LPA receptors. FEBS Lett. 2000 Jul 28;478(1-2):159-65.
• [8] Phosphorothioate analogues of alkyl lysophosphatidic acid as LPA3 receptor-selective agonists. ChemMedChem. 2006 Mar;1(3):376-83.
• [9] Dual activity lysophosphatidic acid receptor pan-antagonist/autotaxin inhibitor reduces breast cancer cell migration in vitro and causes tumor regression in vivo. Cancer Res. 2009 Jul 1;69(13):5441-9.
• [10] Short-chain phosphatidates are subtype-selective antagonists of lysophosphatidic acid receptors. Mol Pharmacol. 2001 Oct;60(4):776-84.
• [11] Targeting lysophosphatidic acid receptor type 1 with Debio 0719 inhibits spontaneous metastasis dissemination of breast cancer cells independently of cell proliferation and angiogenesis. Int J Oncol. 2012 Apr;40(4):1133-41.
• [12] Diversity of lysophosphatidic acid receptor-mediated intracellular calcium signaling in early cortical neurogenesis. J Neurosci. 2010 May 26;30(21):7300-9.
• [13] LPA and its analogs-attractive tools for elucidation of LPA biology and drug development. Curr Med Chem. 2008;15(21):2122-31.
• [14] Pharmacological tools for lysophospholipid GPCRs: development of agonists and antagonists for LPA and S1P receptors. Acta Pharmacol Sin. 2010 Sep;31(9):1213-22.
• [15] Crystal Structure of Antagonist Bound Human Lysophosphatidic Acid Receptor 1. Cell. 2015 Jun 18;161(7):1633-43.
• [16] Activity of 2-substituted lysophosphatidic acid (LPA) analogs at LPA receptors: discovery of a LPA1/LPA3 receptor antagonist. Mol Pharmacol. 2001 Dec;60(6):1173-80.
• [17] Initial structure-activity relationships of lysophosphatidic acid receptor antagonists: discovery of a high-affinity LPA1/LPA3 receptor antagonist. Bioorg Med Chem Lett. 2004 Jun 7;14(11):2735-40.