TY - JOUR
T1 - Discovery of 2,3-Diaminoindole Derivatives as a Novel Class of NOD Antagonists
AU - Russo, Camilla
AU - Russomanno, Pasquale
AU - D’Amore, Vincenzo Maria
AU - Alfano, Antonella Ilenia
AU - Santoro, Federica
AU - Guzelj, Samo
AU - Gobec, Martina
AU - Amato, Jussara
AU - Pagano, Bruno
AU - Marinelli, Luciana
AU - Carotenuto, Alfonso
AU - TRON, Gian Cesare
AU - Di Leva, Francesco Saverio
AU - Jakopin, Žiga
AU - Brancaccio, Diego
AU - Giustiniano, Mariateresa
PY - 2024
Y1 - 2024
N2 - NOD1 and NOD2 are members of the pattern recognition receptors involved in the innate immune response. Overactivation of NOD1 is implicated in inflammatory disorders, multiple sclerosis, and cancer cell metastases. NOD1 antagonists would represent valuable pharmacological tools to gain further insight into protein roles, potentially leading to new therapeutic strategies. We herein report the expansion of the chemical space of NOD1 antagonists via a multicomponent synthetic approach affording a novel chemotype, namely, 2,3-diaminoindoles. These efforts resulted in compound 37, endowed with low micromolar affinity toward NOD1. Importantly, a proof-of-evidence of direct binding to NOD1 of Noditinib-1 and derivative 37 is provided here for the first time. Additionally, the combination of computational studies and NMR-based displacement assays enabled the characterization of the binding modality of 37 to NOD1, thus providing key unprecedented knowledge for the design of potent and selective NOD1 antagonists.
AB - NOD1 and NOD2 are members of the pattern recognition receptors involved in the innate immune response. Overactivation of NOD1 is implicated in inflammatory disorders, multiple sclerosis, and cancer cell metastases. NOD1 antagonists would represent valuable pharmacological tools to gain further insight into protein roles, potentially leading to new therapeutic strategies. We herein report the expansion of the chemical space of NOD1 antagonists via a multicomponent synthetic approach affording a novel chemotype, namely, 2,3-diaminoindoles. These efforts resulted in compound 37, endowed with low micromolar affinity toward NOD1. Importantly, a proof-of-evidence of direct binding to NOD1 of Noditinib-1 and derivative 37 is provided here for the first time. Additionally, the combination of computational studies and NMR-based displacement assays enabled the characterization of the binding modality of 37 to NOD1, thus providing key unprecedented knowledge for the design of potent and selective NOD1 antagonists.
UR - https://iris.uniupo.it/handle/11579/178867
U2 - 10.1021/acs.jmedchem.3c02094
DO - 10.1021/acs.jmedchem.3c02094
M3 - Article
SN - 0022-2623
VL - 67
SP - 3004
EP - 3017
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 4
ER -