Novel Disease Hypotheses for GPR68 (OGR1) Antagonists

Request Number REQ6342515
Due Date May 26, 2017
Request for Proposal Details
Additional Points of Contact
RFP Title
Novel Disease Hypotheses for GPR68 (OGR1) Antagonists
RFP Description

NineSigma, representing Boehringer Ingelheim the global pharmaceutical company, invites proposals for novel disease hypotheses for GPR68 (OGR1) antagonists. Scientists will collaborate with Boehringer Ingelheim and be given access to unique GPR68 antagonist compounds to conduct experiments to test their hypotheses and identify novel diseases, indications or pathways linked to GPR68.


Recently, the metabotropic OGR1-family G protein-coupled (GPCR) receptor, GPR68 (also known as OGR1) has been implicated in pH-sensing homeostasis and appears to regulate inflammatory processes in immune and non-immune cells. GPR68 senses extracellular protons (H+) through imidazole groups on histidine residues located on the extracellular region, triggering phospholipase C/calcium signaling (PLC/Ca2+) through the activation of Gq/11 (Yuan et al., 2014).


Excess extracellular acidosis within tissue microenvironment during human pathology is attributed to several highly regulated pathways. For example, under ischemia or chronic inflammation, the stimulation of anaerobic glycolysis due to hypoxia causes lactate production which in turn leads to increase tissue acidification and changes in physiological pH (Okajima, 2013). Hypoxia in turn, contributes to the molecular regulation of pH-sensing receptor downstream signaling pathways (de Valliere e al., 2016). As such, subtle drops in physiological pH within tissue microenvironments are actively sensed by several pH-sensing receptors, modulating a variety of pro-inflammatory or anti-inflammatory responses in a wide range of cell types (Okajima, 2013).


GPR68 is abundantly expressed in non-hematopoietic and hematopoietic cells, such as epithelial, fibroblast, smooth muscle cells (SMCs), myeloid and lymphoid cells (Okajima, 2013). Recent studies using genetic approaches have coupled GPR68 signaling to multiple cellular functions; including the production of pro-inflammatory and tissue remodeling mediators,osteoclastogenesis, a potential role in wound repair, epithelial barrier function and tumor genesis (Okajima, 2013, Weiß et al., 2017, de Valliere et al., 2015, Yuan et al., 2014). In addition, GPR68 deficient mice have been shown to be protective in several autoimmune, inflammatory and tumor models of disease (D’Souza et al., 2016, de Valliere et al., 2015, Aoki et al., 2013). GPR68 may contribute to the pathogenesis of chronic inflammatory diseases, pharmacological proof of concept is still lacking. Further understanding of the molecular interplays between GPR68 signaling and disease driving pathways can lead to novel therapeutic concepts focused on improving tissue dysfunction toward homeostasis.


Boehringer Ingelheim has created a unique preclinical GPR68 antagonist tool compound. GPR68 antagonists are unprecedented in literature. The compound will be provided free of charge in the amount required for the experiments.


Boehringer Ingelheim’s novel small molecule pharmacological tool combines high binding affinity (IC50 of 20 nM on human GPR68), cross reactivity on mouse GPR68 and a robust reduction of pH-stimulated IL-6 secretion in normal human dermal fibroblasts with an IC50 of 30 nM. Its PK properties in mouse, rat and dog are suitable for once or twice daily oral dosing in acute or sub-chronic in vivo experiments. The compound was shown to be selective versus a diverse panel of off-targets (Eurofin lead profiler screen) and to inhibit only 3 of 290 kinases in an Invitrogen kinase panel (~50% inhibition of GSK3A, GSK4B, HIPK2 at 10 µM). The front-runner GPR68 antagonist is a member of a family of compounds generated in our GPR68 program. Additional compounds have different properties and pharmacological profiles and may be available for sharing.


GPR68 (OGR1) Antagonist Tool Compound

hGPR68 Binding [nM]

20 nM

Ca2+ FLIPR human GPR68 IC50 [nM]

70 nM

Ca2+ FLIPR murine GPR68 IC50 [nM]

50 nM

Reduction of IL-6 secretion from NHDF IC50 [nM]

30 nM

Eurofins Lead Profiler off-target screen @10 µM [hits >50% control]

0 out of 68

Invitrogen kinase panel inhibition @10 µM [hits >50%control]

3 out of 290


Boehringer Ingelheim believes that its unique preclinical tool compounds have a vast opportunity beyond the therapeutic settings that its scientists are currently focusing upon. For this reason Boehringer Ingelheim will provide access to some of its preclinical tool compounds with optimized pharmacological properties from current and past discovery research projects for scientists to probe novel disease biology.



Okajima, Cellular Signalling 25 (2013) 2263–2271

de Valliere et al., Cell. Mol. Gastroenterol. Hepatol. 2 (2016) 796–810

Yuan et al., Int. J. Mol. Sci. 15 (2014) 22365-22373

Weiß et al., Exp. Dermatol. 26 (2017) 127–132

de Valliere et al., Am. J. Physiol. Gastrointest. Liver Physiol. 309(2015) G475–G490

D’Souza et al., PLoS ONE 11 (2016) e0148439

Aoki et al., PLoS ONE 8 (2013) e79985



Key Success Criteria

Boehringer Ingelheim is seeking proposals that have:

  • A strong scientific proposal with a new and compelling scientific idea for GPR68 (OGR1) antagonists in a novel disease indication or pathway
  • A novel, testable working hypothesis distinct from those previously published


Additional key success criteria are:

  • The quality and feasibility of the the existing data and / or the experimental plan that will be used to test the hypothesis
  • The experimental endpoints and how well these can be translated to human disease


If confidential data exists that would strengthen the proposal, the solution provider may indicate that confidential information is available to share under a Confidential Disclosure Agreement (CDA). If Boehringer Ingelheim finds the non‐confidential concept proposal sufficiently interesting, they will execute a CDA for confidential discussions.


Possible Approaches

Our Boehringer Ingelheim is open to all proposals that can fully or partially meet their requirements. 


Preferred Collaboration types
Items to be submitted

Anticipated Project Phases or Project Plan

Phase 1 – Review of Proposals by end June 2017

Phase 2 – Collaborations starting Q3 2017


Submitting a response

  • Click the Response button at the top or bottom of the page.
  • Log in, or register for Ninesights (you will be prompted).
  • Complete the simple response form.
  • Attach additional files of information if you want to.
  • Click Submit


Appropriate responses will be a short 2‐3 page concept proposal and will include only non-confidential information:


  • A new and compelling scientific idea for GPR68 (OGR1) antagonists in a novel disease indication or pathway
  • A novel, comprehensive working hypothesis distinct from those previously published
  • A description of feasible existing / planned in vitro and / or in vivo animal experiments and biological test systems which will be used to test the hypothesis
  • An experimental plan:
    • with a testable hypothesies
    • with clear decision points
    • where the existing / proposed experiments have endpoints that can be translated to human disease
    • including time lines for the duration of the planned experiments and an estimate of the amount of compound to be used
  • Brief overview of the respondent(s)
  • Overview of respondent(s) organization(s)
  • Evidence you have access to a research laboratory, appropriate staff and equipment to conduct the experiments you propose
  • Any IP ownership / policy / freedom to operate
  • A list of the literature publications that have been used for writing the proposal



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