4LV9

Fragment-based Identification of Amides Derived From trans-2-(Pyridin-3-yl)cyclopropanecarboxylic Acid as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)

Summary for 4LV9

• Entry DOI: 10.2210/pdb4lv9/pdb
• Related: 4LVA 4LVB 4LVD 4LVF 4LVG 4M6P 4M6Q
• Descriptor: Nicotinamide phosphoribosyltransferase, 7-chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide, 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: 115311.45

Authors

Giannetti, A.M.,Zheng, X.,Skelton, N.,Wang, W.,Bravo, B.,Feng, Y.,Gunzner-Toste, J.,Ho, Y.,Hua, R.,Wang, C.,Zhao, Q.,Liederer, B.M.,Liu, Y.,O'Brien, T.,Oeh, J.,Sampath, D.,Shen, Y.,Wang, L.,Wu, H.,Xiao, Y.,Yuen, P.,Zak, M.,Zhao, G.,Dragovich, P.S. (deposition date: 2013-07-26, release date: 2013-09-25, Last modification date: 2024-02-28)

Primary citation

Zheng, X.,Bair, K.W.,Bauer, P.,Baumeister, T.,Bowman, K.K.,Buckmelter, A.J.,Caligiuri, M.,Clodfelter, K.H.,Feng, Y.,Han, B.,Ho, Y.C.,Kley, N.,Li, H.,Liang, X.,Liederer, B.M.,Lin, J.,Ly, J.,O'Brien, T.,Oeh, J.,Oh, A.,Reynolds, D.J.,Sampath, D.,Sharma, G.,Skelton, N.,Smith, C.C.,Tremayne, J.,Wang, L.,Wang, W.,Wang, Z.,Wu, H.,Wu, J.,Xiao, Y.,Yang, G.,Yuen, P.W.,Zak, M.,Dragovich, P.S.
Identification of amides derived from 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).
Bioorg.Med.Chem.Lett., 23:5488-5497, 2013

PubMed Abstract: Potent, 1H-pyrazolo[3,4-b]pyridine-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using structure-based design techniques. Many of these compounds exhibited nanomolar antiproliferation activities against human tumor lines in in vitro cell culture experiments, and a representative example (compound 26) demonstrated encouraging in vivo efficacy in a mouse xenograft tumor model derived from the A2780 cell line. This molecule also exhibited reduced rat retinal exposures relative to a previously studied imidazo-pyridine-containing NAMPT inhibitor. Somewhat surprisingly, compound 26 was only weakly active in vitro against mouse and monkey tumor cell lines even though it was a potent inhibitor of NAMPT enzymes derived from these species. The compound also exhibited only minimal effects on in vivo NAD levels in mice, and these changes were considerably less profound than those produced by an imidazo-pyridine-containing NAMPT inhibitor. The crystal structures of compound 26 and the corresponding PRPP-derived ribose adduct in complex with NAMPT were also obtained.

PubMed: 24021463
DOI: 10.1016/j.bmcl.2013.08.074

Experimental method

X-RAY DIFFRACTION (1.807 Å)