Calcium and ion channels play a critical role in neuronal signaling. T-type calcium channels (Cav3.1, 3.2, & 3.3) have unique characteristics whereby they respond to small membrane depolarizations and serve as pacemakers, gating the activity of additional ion channels whose activation results in the firing of neurons. Cav3’s finely-tuned voltage-gated property and pacemaker function mediates the transition from tonic to bust-firing and generates neural “oscillations” between brain nuclei and across their pathways.
Cav3 has increased activity in pathologic conditions. The transition to burst-firing and abnormal oscillatory pattern (“dysrhythmia”) occurs in a number of neurologic disorders, including, but not limited to, essential tremor, Parkinson’s Disease, epilepsy, neuropathic pain, and schizophrenia and rare, pediatric genetic disorders, such as Angelman Syndrome and Dravet Syndrome. Collectively referred to as “thalamocortical dysrhythmias (TCDs),” these diseases are mediated by Cav3, a common pathophysiologic pathway. Central and peripheral biomarkers facilitate in vivo readouts of TCDs and target modulation with Cavion’s Cav3 antagonists.
Despite substantial interest in Cav3 as a target, to date there has been little chemistry progress made to improve upon existing, prototype Cav3 antagonists which demonstrate clinical validation, but are limited as chronic therapeutics. These limitations have hampered the full exploration of the utility of Cav3 antagonists to treat TCDs. With CX-8998, Cavion possesses a potential best-in-class Cav3 antagonist with a superior potency and selectivity profile that is poised to enter Phase 2 clinical study.
Cavion discovered that the T-type calcium channel (Cav3) is essential for external calcium entry in cancer cells. Inhibition of Cav3 hampers a cancer cell’s ability to repair double-strand DNA breaks and causes cancer cell cycle arrest and apoptosis.
A model for the regulation of T-type Ca2+ channels in proliferation: roles in stem cells and cancer.
Gray LS, Schiff D, Macdonald TL. Expert Rev. Anticancer Ther. 2013.