4D0X

Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors

Summary for 4D0X

• Entry DOI: 10.2210/pdb4d0x/pdb
• Related: 4D0W
• Descriptor: TYROSINE-PROTEIN KINASE JAK2, 5-(2-aminopyrimidin-4-yl)-2-[2-chloro-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide, GLYCEROL, ... (4 entities in total)
• Functional Keywords: transferase, drug discovery, protein kinase inhibitors, structure-activity relationship, polycythemia vera, tumour cell proliferation inhibition, anti-cancer agents
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 35671.83

Authors

Canevari, G.,Fasolini, M.,Bertrand, J.,Brasca, M.G.,Nesi, M.,Avanzi, N.,Ballinari, D.,Bandiera, T.,Bindi, S.,Carenzi, D.,Casero, D.,Ceriani, L.,Ciomei, M.,Cirla, A.,Colombo, M.,Cribioli, S.,Cristiani, C.,Della Vedova, F.,Fachin, G.,Felder, E.R.,Galvani, A.,Isacchi, A.,Mirizzi, D.,Motto, I.,Panzeri, A.,Pesenti, E.,Vianello, P.,Gnocchi, P.,Donati, D. (deposition date: 2014-04-30, release date: 2014-07-23, Last modification date: 2024-11-06)

Primary citation

Brasca, M.G.,Nesi, M.,Avanzi, N.,Ballinari, D.,Bandiera, T.,Bertrand, J.,Bindi, S.,Canevari, G.,Carenzi, D.,Casero, D.,Ceriani, L.,Ciomei, M.,Cirla, A.,Colombo, M.,Cribioli, S.,Cristiani, C.,Della Vedova, F.,Fachin, G.,Fasolini, M.,Felder, E.R.,Galvani, A.,Isacchi, A.,Mirizzi, D.,Motto, I.,Panzeri, A.,Pesenti, E.,Vianello, P.,Gnocchi, P.,Donati, D.
Pyrrole-3-Carboxamides as Potent and Selective Jak2 Inhibitors.
Bioorg.Med.Chem., 22:4998-, 2014

PubMed Abstract: We report herein the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed in vivo by typical modulation of known biomarkers, and with a favourable pharmacokinetic and safety profile.

PubMed: 25009002
DOI: 10.1016/J.BMC.2014.06.025

Experimental method

X-RAY DIFFRACTION (1.82 Å)