title: LASSBio-1829 Hydrochloride: Development of a New Orally Active N-Acylhydrazone IKK2 Inhibitor with Anti-inflammatory Properties.
abstract: Inhibitor of nuclear factor κB kinase 2 (IKK2) is suggested to be a potential target for the development of novel anti-inflammatory and anticancer drugs. In this work, we applied structure-based drug design to improve the potency of the inhibitor (E)-N'-(4-nitrobenzylidene)-2-naphthohydrazide (LASSBio-1524, 1 a: IC50 =20 μm). The molecular model built for IKK2 together with the docking methodology employed were able to provide important and consistent information with respect to the structural and chemical inhibitor characteristics that may confer potency to IKK2 inhibitors, providing important guidelines for the development of a new N-acylhydrazone (NAH) derivative. (E)-N'-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)benzylidene)-2-naphthohydrazide hydrochloride (LASSBio-1829 hydrochloride, 10) is a 7-azaindole NAH able to inhibit IKK2 with an IC50 value of 3.8 μm. LASSBio-1829 hydrochloride was found to be active in several pharmacological inflammation tests in vivo, showing its potential as an anti-inflammatory prototype.
authors: Laboratório Nacional de Computação Científica (LNCC/MCTI), Petrópolis, RJ, Brazil.
authors: Isabella A
authors: IA
authors: Guedes
authors: Laboratório de Avaliação e Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas (ICB), Universidade Federal do Rio de Janeiro (UFRJ), 21941-902, Rio de Janeiro, RJ, Brazil.
authors: Rosana H C N
authors: RH
authors: Freitas
authors: Laboratório de Farmacologia da Dor e da Inflamação, ICB, UFRJ, Rio de Janeiro, RJ, Brazil.
authors: Natália M
authors: NM
authors: Cordeiro
authors: Laboratório de Farmacologia da Dor e da Inflamação, ICB, UFRJ, Rio de Janeiro, RJ, Brazil.
authors: Thaís S
authors: TS
authors: do Nascimento
authors: Laboratório de Farmacologia da Dor e da Inflamação, ICB, UFRJ, Rio de Janeiro, RJ, Brazil.
authors: Tayna S
authors: TS
authors: Valerio
authors: Laboratório de Farmacologia da Dor e da Inflamação, ICB, UFRJ, Rio de Janeiro, RJ, Brazil.
authors: Patrícia D
authors: PD
authors: Fernandes
authors: Laboratório Nacional de Computação Científica (LNCC/MCTI), Petrópolis, RJ, Brazil.
authors: Laurent E
authors: LE
authors: Dardenne
authors: Laboratório de Avaliação e Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas (ICB), Universidade Federal do Rio de Janeiro (UFRJ), 21941-902, Rio de Janeiro, RJ, Brazil. cmfraga@ccsdecania.ufrj.br.
authors: Carlos A M
authors: CA
authors: Fraga
mesh_terms: D000284:Administration, Oral; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D001597:Benzylidene Compounds / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009281:Naphthalenes / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001597:Benzylidene Compounds; C000610607:N'-(4-(1H-pyrrolo(2,3-b)pyridin-4-yl)benzylidene)-2-naphthohydrazide hydrochloride; D009281:Naphthalenes; D047428:Protein Kinase Inhibitors; D051550:I-kappa B Kinase; C496560:IKBKB protein, human
keywords: IKK2; N-acylhydrazones; anti-inflammatory agents; molecular docking; structure-based drug design