CFTR Activator, C_act-A1

A cell-permeable, non-toxic aminopyrazolocarbonitrile compound that acts as a potent, selective, reversible and cAMP-independent activator of CFTR-dependent Cl^- channel in airway epithelial cells (EC₅₀ = 1.6 µM in CFTR-expressing Fisher rat thyroid cells). Also shown to activate ΔF508-CFTR in primary CF-HBE cell cultures (EC₅₀ = 3.5 µM). Reported to directly bind to the same site as CFTR_inh-172 (>Cat. No. 219670, >Cat. No. 219674). Does neither elevate intracellular cAMP levels nor appear to have any requirement for cAMP agonist, such as forskolin (Cat. No. 344270, Cat. No. 344282). Shown to additively potentiate the G551D-CFTR Cl^- current activated by forskolin with CFTR potentiator, VX-770. Exerts no effect on either Ca²⁺-activated Cl^- channel (TMEM16A) or intracellular Ca²⁺ levels.

A non-cytotoxic (30 µM for 48 h in human airway epithelial Calu-3 cultures) aminopyrazolocarbonitrile compound that is shown to activate both wt- and ΔF508-CFTR channel activity in a cAMP-independent, reversible, and CFTR_inh-172- (Cat. Nos. 219670 & 219674) blockable (IC₅₀ & IC₁₀₀ = 0.37 & 30 µM, respectively, against 30 µM C_act using Fisher rat thyroid/FRT cells with wt-CFTR) manner, without affecting CaCC (Calcium-activated chloride channel) function or cellular levels of Ca²⁺ and cAMP. The maximum activation inducible by C_act-A1 (EC_max = 13 to 30 µM in Cl^- current induction using in Fisher rat thyroid/FRT and primary human bronchial epithelial/HBE cells) is comparable to that achievable via cAMP stimulation by Forskolin treatment (EC_max = 20 µM; Cat. Nos. 344270 & 34427082), which cannot be further enhanced by Forskolin co-treatment in cells expressing wt-CFTR, although additive effects are seen when C_act-A1 and Forskoklin are applied at suboptimal concentrations to cells with wt-CFTR or when the two drugs are applied at respective EC_max to cells with surface ΔF508-CFTR. Neither C_act-A1 nor Forskolin alone (at 30 µM; and 20 µM;, respectively) can effectively activate FRT with surface G551D-CFTR or primary HNPE (human nasal polyp epithelial) cells with surface G551D/Y1092X-CFTR, while C_act-A1-Forskolin co-treatment results in synergistic activation and maximally achievable activation is reported with a three-drug co-treatment using C_act-A1, Forskolin, and VX-770 (at 30, 20, and 10 µM, respectively).

Cell permeable: yes

Primary Target
CFTR

Reversible: yes

Packaged under inert gas

Toxicity: Standard Handling (A)

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Namkung, W., et al. 2013. Mol. Pharmacol.84, 384.

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany