2. Academic Validation
  3. Identification of compounds acting as negative allosteric modulators of the LPA1 receptor

Identification of compounds acting as negative allosteric modulators of the LPA1 receptor

  • Eur J Pharmacol. 2018 Aug 15;833:8-15. doi: 10.1016/j.ejphar.2018.05.040.
Jonathan Ellery 1,  Louise Dickson 2,  Toni Cheung 3,  Loredana Ciuclan 4,  Peter Bunyard 5,  Stephen Mack 6,  William J Buffham 7,  William Farnaby 8,  Philip Mitchell 9,  Daniel Brown 10,  Richard Isaacs 11,  Matt Barnes 12
Affiliations

Affiliations

  • 1 Takeda Cambridge Ltd., 418 Cambridge Science Park, Cambridge, Cambridgeshire CB4 0PZ, UK. Electronic address: [email protected].
  • 2 Takeda Cambridge Ltd., 418 Cambridge Science Park, Cambridge, Cambridgeshire CB4 0PZ, UK; Cerevance, 418 Cambridge Science Park, Cambridge, Cambridgeshire CB4 0PZ, UK. Electronic address: [email protected].
  • 3 Takeda Cambridge Ltd., 418 Cambridge Science Park, Cambridge, Cambridgeshire CB4 0PZ, UK; Cerevance, 418 Cambridge Science Park, Cambridge, Cambridgeshire CB4 0PZ, UK. Electronic address: [email protected].
  • 4 Takeda Cambridge Ltd., 418 Cambridge Science Park, Cambridge, Cambridgeshire CB4 0PZ, UK; Study Enterprise, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Cambridge, UK. Electronic address: [email protected].
  • 5 Takeda Cambridge Ltd., 418 Cambridge Science Park, Cambridge, Cambridgeshire CB4 0PZ, UK; Redx Immunology, Block 33, Mereside, Alderley Park, Alderley Edge, Macclesfield SK10 4TG, UK. Electronic address: [email protected].
  • 6 Takeda Cambridge Ltd., 418 Cambridge Science Park, Cambridge, Cambridgeshire CB4 0PZ, UK; Convergence Pharmaceuticals, B900, Babraham Research Campus, Babraham, Cambridgeshire CB22 3AT, UK. Electronic address: [email protected].
  • 7 Takeda Cambridge Ltd., 418 Cambridge Science Park, Cambridge, Cambridgeshire CB4 0PZ, UK; Convergence Pharmaceuticals, B900, Babraham Research Campus, Babraham, Cambridgeshire CB22 3AT, UK. Electronic address: [email protected].
  • 8 Takeda Cambridge Ltd., 418 Cambridge Science Park, Cambridge, Cambridgeshire CB4 0PZ, UK; School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK. Electronic address: [email protected].
  • 9 Takeda Cambridge Ltd., 418 Cambridge Science Park, Cambridge, Cambridgeshire CB4 0PZ, UK; Charles River Discovery Research Services UK Limited, Robinson Building, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, UK. Electronic address: [email protected].
  • 10 Molecular Sensing Inc., 111 10th Ave. S. Suite 110, Nashville, TN, USA; Albany Molecular Research Inc., The Conventus Building, 1001 Main Street, Buffalo, NY 14203, USA. Electronic address: [email protected].
  • 11 Molecular Sensing Inc., 111 10th Ave. S. Suite 110, Nashville, TN, USA; Creoptix Inc., 100 Franklin St Fl7, Boston, MA 02110, USA. Electronic address: [email protected].
  • 12 Takeda Cambridge Ltd., 418 Cambridge Science Park, Cambridge, Cambridgeshire CB4 0PZ, UK; Heptares Therapeutics Ltd., BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, UK. Electronic address: [email protected].
PMID: 29807028 DOI: 10.1016/j.ejphar.2018.05.040
Abstract

The Lysophosphatidic Acid 1 Receptor (LPA1 receptor) has been linked to the initiation and progression of a variety of poorly treated fibrotic conditions. Several compounds that have been described as LPA1 receptor antagonists have progressed into clinical trials: 1-(4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]phenyl}phenyl)cyclopropane-1-carboxylic acid (BMS-986202) and 2-{4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzamido}-2,3-dihydro-1H-indene-2-carboxylic acid (SAR-100842). We considered that as LPA1 receptor function is involved in many normal physiological processes, inhibition of specific signalling pathways associated with fibrosis may be therapeutically advantageous. We compared the binding and functional effects of a novel compound; 4-({(Cyclopropylmethyl)[4-(2-fluorophenoxy)benzoyl]amino}methyl}benzoic acid (TAK-615) with BMS-986202 and SAR-100842. Back-scattering interferometry (BSI) was used to show that the apparent affinity of TAK-615 was enhanced in the presence of LPA. The binding signal for BMS-986202 was not detected in the presence of LPA suggesting competition but interestingly the apparent affinity of SAR-100842 was also enhanced in the presence of LPA. Only BMS-986202 was able to fully inhibit the response to LPA in calcium mobilisation, β-arrestin, cAMP, GTPγS and RhoA functional assays. TAK-615 and SAR-100842 showed different inhibitory profiles in the same functional assays. Further binding studies indicated that TAK-615 is not competitive with either SAR-100842 or BMS-986202, suggesting a different site of binding. The results generated with this set of experiments demonstrate that TAK-615 acts as a negative allosteric modulator (NAM) of the LPA1 receptor. Surprisingly we find that SAR-100842 also behaves like a NAM. BMS-986202 on the other hand behaves like an orthosteric antagonist.

Keywords

Backscattering interferometry; Fibrosis; G-protein signalling; LPA(1) receptor; Negative allosteric modulator.

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