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CRAC channels as targets for drug discovery and development
1CalciMedica, Inc., 505 Coast Blvd. South, Suite 202, La Jolla, CA 92037, United States.
Abstract:
Calcium release-activated calcium (CRAC) channels have been the target of drug discovery for many years. The identification of STIM and Orai proteins as key components of CRAC channels greatly facilitated this process because their co-expression in cell lines produced electrophysiological currents (ICRAC) much larger than those in native cells, making it easier to confirm and characterize the effects of modulatory compounds. A driving force in the quest for CRAC channel drugs has been the immunocompromised phenotype displayed by humans and mice with null or loss-of-function mutations in STIM1 or Orai1, suggesting that CRAC channel inhibitors could be useful therapeutics for autoimmune or inflammatory conditions. Emerging data also suggests that other therapeutic conditions may benefit from CRAC channel inhibition. However, only recently have CRAC channel inhibitors reached clinical trials. This review discusses the challenges associated with drug discovery and development on CRAC channels and the approaches employed to date, as well as the results, starting from initial high-throughput screens for CRAC channel modulators and progressing through target selection and justification, descriptions of pharmacological, safety and toxicological profiles of compounds, and finally the entry of CRAC channel inhibitors into clinical trials.
Insights
Drug discovery for calcium release-activated calcium (CRAC) channels, crucial for immune function, has advanced with STIM/Orai identification. CRAC channel inhibitors are now entering clinical trials for inflammatory diseases.
Area of Science:
- Molecular Biology
- Pharmacology
- Immunology
Background:
- Calcium release-activated calcium (CRAC) channels are critical for cellular calcium influx and immune cell function.
- STIM and Orai proteins are key components of CRAC channels, facilitating their study and drug development.
- Loss-of-function mutations in STIM1 or Orai1 cause immunocompromised phenotypes, highlighting CRAC channels as therapeutic targets for autoimmune and inflammatory conditions.
Purpose of the Study:
- To review the challenges and approaches in the drug discovery and development of CRAC channel inhibitors.
- To discuss the progression from initial screening to clinical trials for CRAC channel modulators.
- To explore the therapeutic potential of CRAC channel inhibition beyond inflammatory diseases.
Main Methods:
- High-throughput screening (HTS) for CRAC channel modulators.
- Target selection and validation based on genetic and phenotypic data.
- Pharmacological characterization, including safety and toxicological profiling of compounds.
Main Results:
- Identification of STIM and Orai proteins enabled robust electrophysiological characterization of CRAC channel activity.
- CRAC channel inhibitors have progressed through preclinical development, with some now entering clinical trials.
- The therapeutic potential of CRAC channel inhibition is expanding to various conditions.
Conclusions:
- Despite significant challenges, CRAC channel drug discovery has advanced considerably, leading to clinical translation.
- STIM/Orai-based CRAC channel modulators represent a promising therapeutic strategy for inflammatory and potentially other diseases.
- Continued research into CRAC channel pharmacology and physiology is essential for optimizing therapeutic strategies.
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