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About the CRACM Channel Inhibitor 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
allow electrically excitable cells, such as neurons or muscle cells, to
discharge. Drugs that modulate these ion channels form a successful therapeutic
category, with dozens of such drugs on the market and commonly prescribed for
the treatment of various neurological and cardiovascular disorders.
The CRACM program targets an ion channel known as the calcium release-activated
calcium modulator (“CRACM”) channel, which is believed to play a key role
specifically in immune cells rather than in neurons or muscle cells. CRACM
channels regulate the calcium signaling pathway driving immune cell activation
and secretion of TNF-alpha, IL-2, and other inflammatory factors.
The therapeutic importance of inhibiting this calcium signaling pathway has been
demonstrated through clinical experience with calcineurin inhibitors, such as
cyclosporine, which are potent immunomodulators but have significant toxicities
due to the broad role calcineurin plays in non-immune cells.
In contrast to calcineurin, CRACM channels 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.
We have identified CRACM channel inhibitors that have shown strong
anti-inflammatory 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 rheumatoid
arthritis, asthma, chronic obstructive pulmonary disease (COPD), allergy,
transplant rejection, and other autoimmune diseases and inflammatory
conditions.
Partnership with Roche
In December 2008, Synta entered into a collaboration with Roche to discover,
develop, and commercialize CRACM inhibitors. Under the terms of the agreement,
Roche will fund research to be conducted by Synta during an initial two-year
research period. Roche will receive worldwide rights to develop and
commercialize certain products identified prior to the end of this research
period. All preclinical, clinical, and commercial costs will be paid by Roche.
Synta will receive development milestones, commercial milestones, and tiered
royalties on sales of all approved, marketed products. For additional details
click here.
References
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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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Aarts, M. et al. A key role for TRPM7 channels in anoxic neuronal death. Cell,
2003 Dec 26;115(7):863-77.
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Prakriya, M., Lewis, R.S. CRAC channels: activation, permeation, and the search
for a molecular identity. Cell Calcium, 2003 May-Jun;33(5-6):311-21.
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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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Lewis, R.S. Calcium signaling mechanisms in T lymphocytes. Annu. Rev. Immunol.
19, 497-521 (2001).
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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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