5upe

From Proteopedia

Crystal structure of human NAMPT with isoindoline urea inhibitor compound 5

PDB ID 5upe

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Structural highlights

5upe is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.93Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NAMPT_HUMAN Catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD. It is the rate limiting component in the mammalian NAD biosynthesis pathway (By similarity).

Publication Abstract from PubMed

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.

SAR and characterization of non-substrate isoindoline urea inhibitors of nicotinamide phosphoribosyltransferase (NAMPT).,Curtin ML, Heyman HR, Clark RF, Sorensen BK, Doherty GA, Hansen TM, Frey RR, Sarris KA, Aguirre AL, Shrestha A, Tu N, Woller K, Pliushchev MA, Sweis RF, Cheng M, Wilsbacher JL, Kovar PJ, Guo J, Cheng D, Longenecker KL, Raich D, Korepanova AV, Soni NB, Algire MA, Richardson PL, Marin VL, Badagnani I, Vasudevan A, Buchanan FG, Maag D, Chiang GG, Tse C, Michaelides MR Bioorg Med Chem Lett. 2017 Aug 1;27(15):3317-3325. doi:, 10.1016/j.bmcl.2017.06.018. Epub 2017 Jun 14. PMID:28610984^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Curtin ML, Heyman HR, Clark RF, Sorensen BK, Doherty GA, Hansen TM, Frey RR, Sarris KA, Aguirre AL, Shrestha A, Tu N, Woller K, Pliushchev MA, Sweis RF, Cheng M, Wilsbacher JL, Kovar PJ, Guo J, Cheng D, Longenecker KL, Raich D, Korepanova AV, Soni NB, Algire MA, Richardson PL, Marin VL, Badagnani I, Vasudevan A, Buchanan FG, Maag D, Chiang GG, Tse C, Michaelides MR. SAR and characterization of non-substrate isoindoline urea inhibitors of nicotinamide phosphoribosyltransferase (NAMPT). Bioorg Med Chem Lett. 2017 Aug 1;27(15):3317-3325. doi:, 10.1016/j.bmcl.2017.06.018. Epub 2017 Jun 14. PMID:28610984 doi:http://dx.doi.org/10.1016/j.bmcl.2017.06.018