57728-67-3Relevant articles and documents
Illuminating a Dark Kinase: Structure-Guided Design, Synthesis, and Evaluation of a Potent Nek1 Inhibitor and Its Effects on the Embryonic Zebrafish Pronephros
Baumann, Georg,Meckel, Tobias,B?hm, Kevin,Shih, Yung-Hsin,Dickhaut, Mirco,Reichardt, Torben,Pilakowski, Johannes,Pehl, Ulrich,Schmidt, Boris
, p. 1265 - 1282 (2021/04/12)
NIMA-related kinase 1 (Nek1) has lately garnered attention for its widespread function in ciliogenesis, apoptosis, and the DNA-damage response. Despite its involvement in various diseases and its potential as a cancer drug target, no directed medicinal chemistry efforts toward inhibitors against this dark kinase are published. Here, we report the structure-guided design of a potent small-molecule Nek1 inhibitor, starting from a scaffold identified by kinase cross-screening analysis. Seven lead compounds were identified in silico and evaluated for their inhibitory activity. The top compound, 10f, was further profiled for efficacy, toxicity, and bioavailability in a zebrafish polycystic kidney disease model. Administration of 10f caused the expansion of fluorescence-labeled proximal convoluted tubules, supporting our hypothesis that Nek1-inhibition causes cystic kidneys in zebrafish embryos. Compound 10f displayed insignificant inhibition in 48 of 50 kinases in a selectivity test panel. The findings provide a powerful tool to further elucidate the function and pharmacology of this neglected kinase.
Discovery of 1,1′-Biphenyl-4-sulfonamides as a New Class of Potent and Selective Carbonic Anhydrase XIV Inhibitors
La Regina, Giuseppe,Coluccia, Antonio,Famiglini, Valeria,Pelliccia, Sveva,Monti, Ludovica,Vullo, Daniela,Nuti, Elisa,Alterio, Vincenzo,De Simone, Giuseppina,Monti, Simona Maria,Pan, Peiwen,Parkkila, Seppo,Supuran, Claudiu T.,Rossello, Armando,Silvestri, Romano
supporting information, p. 8564 - 8572 (2015/11/24)
New 1,1′-biphenylsulfonamides were synthesized and evaluated as inhibitors of the ubiquitous human carbonic anhydrase isoforms I, II, IX, XII, and XIV using acetazolamide (AAZ) as reference compound. The sulfonamides 1-21 inhibited all the isoforms, with Ki values in the nanomolar range of concentration, and were superior to AAZ against all of them. X-ray crystallography and molecular modeling studies on the adducts that compound 20, the most potent hCA XIV inhibitor of the series (Ki = 0.26 nM), formed with the five hCAs, provided insight into the molecular determinants responsible for the high affinity of this molecule toward the target enzymes. The results pave the way to the development of 1.1′-biphenylsulfonamides as a new class of highy potent hCA XIV inhibitors.
Imidazole pyrimidine amides as potent, orally bioavailable cyclin-dependent kinase inhibitors
Jones, Clifford D.,Andrews, David M.,Barker, Andrew J.,Blades, Kevin,Byth, Kate F.,Finlay, M. Raymond V.,Geh, Catherine,Green, Clive P.,Johannsen, Marie,Walker, Mike,Weir, Hazel M.
body text, p. 6486 - 6489 (2009/10/01)
The development of a novel series of imidazole pyrimidine amides as cyclin-dependent kinase (CDK) inhibitors is described. The series was found to have much improved CDK2 inhibition and potent in vitro anti-proliferative effects against cancer cell lines. Control of overall lipophilicity was important to achieve good in vitro potency along with acceptable physiochemical properties and margins against inhibition of both CYP isoforms and the hERG potassium ion channel. A compound with an attractive overall balance of properties was profiled in vivo and possessed suitable physiochemical and pharmacokinetic profiles for oral dosing.