4LTS

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

Summary for 4LTS

• Entry DOI: 10.2210/pdb4lts/pdb
• Related: 4LWW
• Descriptor: Nicotinamide phosphoribosyltransferase, 2-cyano-1-pyridin-4-yl-3-(4-{[3-(trifluoromethoxy)phenyl]sulfonyl}benzyl)guanidine, PHOSPHATE ION, ... (5 entities in total)
• Functional Keywords: transferase, 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: 115584.19

Authors

Zheng, X.,Baumeister, T.,Buckmelter, A.J.,Caligiuri, M.,Clodfelter, K.H.,Han, B.,Ho, Y.,Kley, N.,Lin, J.,Reynoids, D.J.,Sharma, G.,Smith, C.C.,Wang, Z.,Dragovich, P.S.,Oh, A.,Wang, W.,Zak, M.,Wang, L.,Yuen, P.,Bair, K.W. (deposition date: 2013-07-23, release date: 2013-12-25, Last modification date: 2023-09-20)

Primary citation

Zheng, 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

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

Experimental method

X-RAY DIFFRACTION (1.692 Å)