TRAM-34

TRAM-34 is a selective and potent inhibitor of the intermediate-conductance Ca2+-activated K+ channel (IKCa1, KCa3.1) with Kd of 20 nM. Unlike clotrimazole, TRAM-34 dose not inhibit mammalian cytochrome P450 enzyme (CYP3A4). TRAM-34 displays >200-fold selectivity for IKCa1 over Kv, BKCa, SKCa, Na, CRAC, and chloride channels. TRAM-34 does not exhibit toxicity against a variety of cell lines in vitro or cause obvious deleterious changes in a limited short-term acute toxicity study in rodents. TRAM-34 significantly inhibits the reactivation process of human lymphocytes by mitogenic stimuli, and when in combination with cyclosporin A suppresses T-cell mitogenesis more potently than either compound alone. TRAM-34 significantly inhibits EGF-induced IKCa1 up-regulation, and EGF-stimulated proliferation of A7r5 cells. TRAM-34 treatment at 120 mg/kg/day significantly reduces intimal hyperplasia in rat model of balloon catheter injury (BCI). TRAM-34 inhibits human endometrial cancer (EC) cell proliferation, arrests its cell cycle at G0/G1 phase, and suppresses the development of EC tumors in nude mice. By specifically targeting IKCa1, TRAM-34 treatment inhibits the prostate cancer (PCa) cell proliferation in a dose-dependent manner, involving growth arrest and an accumulation of p21Cip1.