5KIT

Crystal Structure of Nicotinamide Phosphoribosyltransferase (Nampt) in Complex with Inhibitors 37

Summary for 5KIT

• Entry DOI: 10.2210/pdb5kit/pdb
• Descriptor: Nicotinamide phosphoribosyltransferase, ~{tert}-butyl (2~{S})-2-[(1,3-dihydropyrrolo[3,4-c]pyridin-2-ylcarbonylamino)methyl]-6-azaspiro[2.5]octane-6-carboxylate, 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: 113091.29

Authors

Li, D.,Wang, W. (deposition date: 2016-06-17, release date: 2016-08-31, Last modification date: 2024-03-06)

Primary citation

Zak, M.,Yuen, P.W.,Liu, X.,Patel, S.,Sampath, D.,Oeh, J.,Liederer, B.M.,Wang, W.,O'Brien, T.,Xiao, Y.,Skelton, N.,Hua, R.,Sodhi, J.,Wang, Y.,Zhang, L.,Zhao, G.,Zheng, X.,Ho, Y.C.,Bair, K.W.,Dragovich, P.S.
Minimizing CYP2C9 Inhibition of Exposed-Pyridine NAMPT (Nicotinamide Phosphoribosyltransferase) Inhibitors.
J.Med.Chem., 59:8345-8368, 2016

PubMed Abstract: NAMPT inhibitors may show potential as therapeutics for oncology. Throughout our NAMPT inhibitor program, we found that exposed pyridines or related heterocyclic systems in the left-hand portion of the inhibitors are necessary pharmacophores for potent cellular NAMPT inhibition. However, when combined with a benzyl group in the center of the inhibitors, such pyridine-like moieties also led to consistent and potent inhibition of CYP2C9. In an attempt to reduce CYP2C9 inhibition, a parallel synthesis approach was used to identify central benzyl group replacements with increased Fsp3. A spirocyclic central motif was thus discovered that was combined with left-hand pyridines (or pyridine-like systems) to provide cellularly potent NAMPT inhibitors with minimal CYP2C9 inhibition. Further optimization of potency and ADME properties led to the discovery of compound 68, a highly potent NAMPT inhibitor with outstanding efficacy in a mouse tumor xenograft model and lacking measurable CYP2C9 inhibition at the concentrations tested.

PubMed: 27541271
DOI: 10.1021/acs.jmedchem.6b00697

Experimental method

X-RAY DIFFRACTION (1.6 Å)