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Program Overview
About the Synta CRACM Program
Ion channels, the gateways in cell membranes that regulate the flow of ions into
and out of cells, play important roles in cell signaling. Certain ion channels
are essential for allowing electrically excitable cells, such as neurons or
muscle cells, to fire. Drugs that modulate these ion channels are widely used
to treat various neurological and cardiovascular disorders.
The CRACM program targets an ion channel known as the calcium release-activated
calcium modulator (“CRACM”) channel, which plays a key role in immune cells,
e.g. T cells, rather than in neurons or muscle cells. CRACM channels regulate
the calcium signaling pathway driving immune cell secretion of key
pro-inflammatory factors such as TNF-alpha and IL-2.
Inhibitors of the CRACM channel can reduce immune cell production of
pro-inflammatory factors, providing a novel way to treat serious autoimmune or
inflammatory conditions. The effectiveness of this approach has been validated
by the calcineurin inhibitors, such as cyclosporine, which also modulate
calcium signaling in immune cells, but do so by suppressing a protein that is
present more broadly in the body, not just in immune cells. While calcineurin
inhibitors have been shown to be potent immunosuppressants, they are limited in
their use by significant toxicities, believed to be related to the broad
presence of their target in the body.
The CRACM channels, in contrast, are believed to be critical exclusively to
immune cell function. CRACM inhibitors therefore have the potential to achieve
potent anti-inflammatory activity with an improved safety profile, creating a
new category of disease-modifying agents comparable to biologic agents, such as
TNF-alpha inhibitors, but orally available. Applications include serious
inflammatory diseases such as rheumatoid arthritis, psoriasis, COPD, transplant
rejection, and severe allergy or asthma.
Synta has developed novel, small molecule inhibitors of CRACM ion channels
expressed on immune cells. Our CRACM ion channel inhibitors have shown strong
antiinflammatory activity in preclinical studies both in vitro and in vivo,
inhibiting T cell and mast cell activity, including cytokine release,
degranulation, and immune cell proliferation. Potential applications include a
wide range of inflammatory diseases and disorders for which modulating T cell
and mast cell function has been shown to be critical, including RA, asthma,
chronic obstructive pulmonary disease, or COPD, allergy, transplant rejection,
and other autoimmune diseases and inflammatory conditions.
As part of our strategic alliance with Roche, Roche is advancing several
compounds in preclinical development. We also have several CRACM inhibitors
that are not licensed to Roche in lead optimization. Because there are a number
of CRACM ion channel targets on immune cells, we believe that our next
generation CRACM inhibitor compounds could potentially apply to different
immune system diseases and address distinct therapeutic areas, such as RA,
allergy, asthma, and transplant rejection.
Partnership with Roche
In December 2008, Synta entered into a collaboration with Roche to discover,
develop, and commercialize CRACM inhibitors, under which Roche agreed to fund
research to be conducted by Synta during a two-year research period. The
research term concluded on December 31, 2010. Roche continues to have
worldwide rights to develop and commercialize certain products identified prior
to the end of this research period. All remaining rights and intellectual
property are retained by Synta.
References
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Feske S.
CRAC channelopathies. Pflugers Arch. 2010 Jul;460(2):417-35.
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Hogan PG, Lewis RS, Rao A.
Molecular basis of calcium signaling in lymphocytes: STIM and ORAI.
Annu Rev Immunol. 2010 Mar;28:491-533.
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Vig, M., and Kinet, J.P. Calcium signaling in immune cells. Nat. Immunol. 10,
21-7 (2009).
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Feske, S., Prakriya, M., Rao, A., and Lewis, R.S. A severe defect in CRAC Ca2+
channel activation and altered K+ channel gating in T cells from
immunodeficient patients. J. Exp. Med. 202, 651-62 (2005).
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Michael Xie, Mats H Holmqvist and Albert Y Hsia.
Ion channel drug discovery expands into new disease areas. Current Drug
Discovery, April 2004, 31 - 33.
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Montell, C., Birnbaumer, L. and Flockerzi, V. The TRP channels, a remarkable
functional family. Cell, March 2002, 108(5):595–598.
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Cahalan, M.D., and Chandy, K.G. Ion channels in the immune system as targets for
immunosuppression. Curr. Opin. Biotechnol. 8, 749-56 (1997).
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Hoth, M., and Penner, R. Depletion of intracellular calcium stores activates a
calcium current in mast cells. Nature. 355, 353-6 (1992).
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