SGLT6 (SLC5A11, SMIT2) inhibitor

Target protein: 
SGLT6

Information

Call for collaboration proposals

Boehringer Ingelheim invites scientists to submit their proposals for novel indications or diseases for its potent and selective SGLT6 (SLC5A11, SMIT2) inhibitor.

The partnership will include privileged access to an unprecedented, potent and selective SGLT6 antagonist compound which has not been published so far. Additional compounds having differentiated properties and pharmacological profiles may also be available for sharing on request. Funding of up to 200.000 Euro will be available upon request and shall be outlined in the submission proposal.

Collaborating scientists will benefit from direct access to Boehringer Ingelheim’s drug discovery and validation capabilities.

The opportunity bears the potential for cutting edge publication of the research at conferences and in refereed journals as well as the opportunity to retain IP or file joint IP on the validated disease hypothesis.



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Target information

Through their control of many essential physiological functions, such as nutrient uptake, solute carrier (SLC) proteins have been recognized as attractive drug targets. Nonetheless, the role(s) of many of these solute carriers remains unexplored [1]. Sodium glucose cotransporters (SGLT) typically facilitate monosaccharide transport across cellular membranes [2]. SGLT6 (SLC5A11) also known as SMIT2, has the lowest amino acid identity of the SGLTs with human SGLT1 (50%) and preferentially transports inositol over glucose in a Na+ dependent manner [3, 4]. In contrast to SMIT1 (SLC5A3), SGLT6 has a more limited tissue distribution in humans with expression in the CNS, small intestine and kidney being prominent. By influencing inositol concentrations in many metabolic pathways, SMITs may represent promising targets for a number of diseases [5].

In-Vitro Activity

The small molecule SGLT6 inhibitor shows an IC50 of 1 nM on 14C-myo-inositol uptake in HEK293 cells overexpressing human SGLT6 [6].

Assay

IC50 [nM]

hSGLT6 (14C-myo-inositol uptake in HEK293 cells overexpressing human SGLT6)

~1

hSGLT1 (14C-α-methyl glucopyranoside uptake in HEK293 cells overexpressing human SGLT1)

700

hSGLT2 (14C-α-methyl glucopyranoside uptake in HEK293 cells overexpressing human SGLT2)

35

dSMIT1 (14C-myo-inositol uptake in endogenous dog MDCK cells)

1090

In-vitro DMPK parameters

The SGLT6 inhibitor has low solubility in water at neutral pH and high permeability in caco-2 and MDCK assays.

In-vivo DMPK parameters

PK properties in rodents are suitable for once or twice daily oral dosing in acute or sub-chronic in vivo experiments.

Selectivity

The SGLT6 inhibitor shows moderate selectivity versus human SGLT2 (~35 fold) but high selectivity versus human SGLT1 (~700 fold) and dog SMIT1 (>1000 fold). A modified IRWIN test in mice showed no side-effects up to a 30 mg/kg dose. The compound was also shown to be selective versus a diverse panel of off-targets (Eurofin lead profiler screen at 10 µM).

Supplementary data

Additional compounds having differentiated properties and pharmacological profiles may also be available for sharing on request.

Summary

We share an unprecedented, potent and selective SGLT6 inhibitor for collaborative research on novel disease indications. This tool compound is brain penetrant and shows pharmacokinetic (PK) properties that are suitable for in vivo testing in rodents. Additional compounds having differentiated properties and pharmacological profiles may also be available for sharing on request. We invite scientists to submit proposals containing a testable hypothesis using our SGLT6 inhibitors.
Submissions for collaborations can only be considered if they arrive no later than February 28, 2018 23.59 pm PST.

References

  1. A Call for Systematic Research on Solute Carriers

    Cesar-Razquin et al.

    Cell 2015;162(3):478-487.

  2. Functional characterisation of human SGLT-5 as a novel kidney-specific sodium-dependent sugar transporter

    Grempler et al.

    FEBS Lett. 2012;586(3):248-253.

  3. Glucose transport families SLC5 and SLC50

    Wright

    Mol. Aspects Med. 2013;34(2-3):183-196.

  4. Human sodium/inositol cotransporter 2 (SMIT2) transports inositols but not glucose in L6 cells

    Lin et al.

    Arch. Biochem. Biophys. 2009;481(2):197-201.

  5. Inositol transport proteins

    Schneider

    FEBS Lett. 2015;589(10):1049-1058.

  6. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors

    Grempler et al.

    Diabetes Obes. Metab. 2012;14(1):83-90.