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4LWW

Discovery of Potent and Efficacious Cyanoguanidine-containing Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors

Summary for 4LWW
Entry DOI10.2210/pdb4lww/pdb
Related4LTS
DescriptorNicotinamide phosphoribosyltransferase, N-(4-(phenylsulfonyl)benzyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide, PHOSPHATE ION, ... (5 entities in total)
Functional Keywordstransferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
Biological sourceHomo sapiens (human)
Cellular locationCytoplasm (By similarity): P43490
Total number of polymer chains2
Total formula weight116226.81
Authors
Primary citationZheng, X.,Baumeister, T.,Buckmelter, A.J.,Caligiuri, M.,Clodfelter, K.H.,Han, B.,Ho, Y.C.,Kley, N.,Lin, J.,Reynolds, D.J.,Sharma, G.,Smith, C.C.,Wang, Z.,Dragovich, P.S.,Oh, A.,Wang, W.,Zak, M.,Wang, Y.,Yuen, P.W.,Bair, K.W.
Discovery of potent and efficacious cyanoguanidine-containing nicotinamide phosphoribosyltransferase (Nampt) inhibitors.
Bioorg.Med.Chem.Lett., 24:337-343, 2014
Cited by
PubMed Abstract: A co-crystal structure of amide-containing compound (4) in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein and molecular modeling were utilized to design and discover a potent novel cyanoguanidine-containing inhibitor bearing a sulfone moiety (5, Nampt Biochemical IC50=2.5nM, A2780 cell proliferation IC50=9.7nM). Further SAR exploration identified several additional cyanoguanidine-containing compounds with high potency and good microsomal stability. Among these, compound 15 was selected for in vivo profiling and demonstrated good oral exposure in mice. It also exhibited excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model. The co-crystal structure of this compound in complex with the NAMPT protein was also determined.
PubMed: 24279990
DOI: 10.1016/j.bmcl.2013.11.006
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.641 Å)
Structure validation

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