ABCMdb

PMID: 16472140

Becq F
On the discovery and development of CFTR chloride channel activators.
Curr Pharm Des. 2006;12(4):471-84., [PubMed]

Sentences

No. Mutations Sentence Comment

38 ABCC7 p.Trp1282* ABCC7 p.Gly542* Corresponding proteins are degraded rapidly or alternatively no protein is produced (e.g. stop mutations: W1282X, G542X). Login to comment 45 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp The glycine-to- aspartic acid missense mutations G551D and G1349D are class III mutations located within the signature sequence LSGGQ in NBD1 and LSHGH in NBD2, respectively [20]. Login to comment 46 ABCC7 p.Gly551Asp G551D is one of the five most frequent CF mutations with a frequency of 2-5% depending of the population of origin. Login to comment 50 ABCC7 p.Arg117His ABCC7 p.Arg334Trp With a class IV mutation (e.g. R117H, R334W, R234P) CFTR processing to the apical membrane and regulation by cAMP and PKA are not altered. Login to comment 52 ABCC7 p.Pro574His ABCC7 p.Ala455Glu Class V mutations (e.g. A455E, P574H) produce functional proteins with normal Cl-channel activity and regulation but at reduced rate of synthesis [19]. Login to comment 175 ABCC7 p.Gly551Asp ABCC7 p.Pro574His ABCC7 p.Lys1250Ala Importantly, NS004 is a modulator of several mutated forms of CFTR; P574H [60], K1250A [61], delF508 [31, 35, 61] and G551D [59]. Login to comment 178 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp In G551D-CFTR expressing CHO cells, in the presence of 10 µM forskolin, NS004 stimulated G551D-CFTR activity in a dose-dependent manner with an EC50 of 1.5 µM [59]. Login to comment 180 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp By contrast to genistein (see below), no inhibitory effect was observed at high concentrations of NS004 for both wtand G551D-CFTR suggesting that NS004 is not an allosteric activator [59]. Login to comment 207 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp By contrast, the response of the two mutants G1349D- and G551D-CFTR to genistein is dramatically altered [39]. Login to comment 208 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp ABCC7 p.Gly1349Asp Genistein is not able to stimulate G1349D- and CFTR bearing the double mutation G551D/G1349D whereas genistein stimulates G551D-CFTR [38, 39, 69] without any inhibition at high concentration [38, 39]. Login to comment 216 ABCC7 p.Gly551Asp The best agent found was UCCF-0339 (Fig. 3) able to activate wt-CFTR with a Kd of 1.7 µM. UCCF-339 appears to be slightly more potent than apigenin (Kd of 4 µM) on wild-type but on the contrary to apigenin did not activate the mutant G551D [70]. Login to comment 220 ABCC7 p.Gly551Asp Activation of CFTR by Benzoquinolizinium Derivatives In 1999 screening of a small library of heterocycle agents identified the benzoquinolizinium family (Fig. 5) of agents as activators of wt-CFTR [40] and later of the mutant G551D [71] and potent correctors of the abnormal trafficking of delF508-CFTR [50, 72]. Login to comment 221 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp A second SAR study was conducted with a series of benzo[c]quinolizinium and benzo[f]indolo[2, 3-a]quinolizinium salts and generated many derivatives that have been tested on both wtand G551D-CFTR chloride channel activity [46]. Login to comment 241 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp This compound is the most potent agent of the series, active with the same efficacy on both wtand G551D-CFTR. Login to comment 246 ABCC7 p.Gly551Asp Additional experiments also showed that MPB-91 did not compete with the ATP binding, did not modulate the ATPase activity at NBD1 and NBD2 and had no significant effect on the reduced ATPase activity of G551D-NBD1 [71]. Login to comment 254 ABCC7 p.Gly551Asp The therapeutic potential for CF of MPBs was demonstrated following studies conducted on delF508-CFTR and G551D-CFTR. Login to comment 255 ABCC7 p.Gly551Asp For example, MPB-91 and MPB-104 but not MPB-07 activated G551D-CFTR [46, 71]. Login to comment 263 ABCC7 p.Gly551Asp Further studies on the correlation between the structure of MPB and their effects will be needed but it is possible that part of the molecule that is common to MPB-07, MPB-91 and MPB-104 is required to interact with delF508-CFTR trafficking whereas an other part allows the activation of G551D-CFTR and Kir6.2 channels. Login to comment 283 ABCC7 p.Gly551Asp Unfortunately, the compounds have no effect on G551D-CFTR [81]. Login to comment 288 ABCC7 p.Gly551Asp A trifluoro- methylphenylbenzamine activated the CF-causing mutant G551D with a Kd > 10µM [47]. Login to comment