5UPF

Crystal structure of human NAMPT with isoindoline urea inhibitor compound 53

Summary for 5UPF

• Entry DOI: 10.2210/pdb5upf/pdb
• Related: 5UPE
• Descriptor: Nicotinamide phosphoribosyltransferase, 5-fluoro-N-{4-[1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl]phenyl}-2H-isoindole-2-carboxamide (3 entities in total)
• Functional Keywords: nampt inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P43490
• Total number of polymer chains: 2
• Total formula weight: 114030.76

Authors

Longenecker, K.L.,Raich, D.,Korepanova, A.V. (deposition date: 2017-02-02, release date: 2017-06-28, Last modification date: 2023-10-04)

Primary citation

Curtin, M.L.,Heyman, H.R.,Clark, R.F.,Sorensen, B.K.,Doherty, G.A.,Hansen, T.M.,Frey, R.R.,Sarris, K.A.,Aguirre, A.L.,Shrestha, A.,Tu, N.,Woller, K.,Pliushchev, M.A.,Sweis, R.F.,Cheng, M.,Wilsbacher, J.L.,Kovar, P.J.,Guo, J.,Cheng, D.,Longenecker, K.L.,Raich, D.,Korepanova, A.V.,Soni, N.B.,Algire, M.A.,Richardson, P.L.,Marin, V.L.,Badagnani, I.,Vasudevan, A.,Buchanan, F.G.,Maag, D.,Chiang, G.G.,Tse, C.,Michaelides, M.R.
SAR and characterization of non-substrate isoindoline urea inhibitors of nicotinamide phosphoribosyltransferase (NAMPT).
Bioorg. Med. Chem. Lett., 27:3317-3325, 2017

PubMed Abstract: Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.

PubMed: 28610984
DOI: 10.1016/j.bmcl.2017.06.018

Experimental method

X-RAY DIFFRACTION (1.69 Å)