Discovery of potent and efficacious urea-containing nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with reduced CYP2C9 inhibition properties

Gunzner-Toste, Janet; Zhao, Gui‐Ling; Bauer, Paul; Baumeister, Timm; Buckmelter, Alexandre J.; Caligiuri, Maureen; Clodfelter, Karl H.; Fu, Bang; Han, Bingsong; Ho, Yew Kam; Kley, Nikolai; Liang, Xiaorong; Liederer, Bianca M.; Lin, Jian; Mukadam, Sophie; O’Brien, Thomas G.; Oh, Angela; Reynolds, Dominic J.; Sharma, Geeta; Skelton, Nicholas J.; Smith, Chase C.; Sodhi, Jasleen K.; Wang, Weiru; Wang, Zhongguo; Xiao, Yang; Yuen, Po‐wai; Zak, Mark; Zhang, Lei; Zheng, Xiaozhang; Bair, Kenneth W.; Dragovich, Peter S.

doi:10.1016/j.bmcl.2013.04.040

Cited by 37 publications

(29 citation statements)

References 27 publications

(4 reference statements)

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“…The H191 imidazole ring forms a herringbone stacking interaction with the GNE-618 phenyl linker moiety. The same interaction is observed for other bi-aryl sulfone inhibitors [18] - [20] . The stacking interaction defined the orientation of the inhibitor linker moiety inside the tunnel passage and oriented the inhibitor's terminal group to exit the tunnel.…”

Section: Resultssupporting

confidence: 73%

Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors

Wang¹,

Elkins²,

Oh³

et al. 2014

PLoS ONE

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Inhibiting NAD biosynthesis by blocking the function of nicotinamide phosphoribosyl transferase (NAMPT) is an attractive therapeutic strategy for targeting tumor metabolism. However, the development of drug resistance commonly limits the efficacy of cancer therapeutics. This study identifies mutations in NAMPT that confer resistance to a novel NAMPT inhibitor, GNE-618, in cell culture and in vivo, thus demonstrating that the cytotoxicity of GNE-618 is on target. We determine the crystal structures of six NAMPT mutants in the apo form and in complex with various inhibitors and use cellular, biochemical and structural data to elucidate two resistance mechanisms. One is the surprising finding of allosteric modulation by mutation of residue Ser165, resulting in unwinding of an α-helix that binds the NAMPT substrate 5-phosphoribosyl-1-pyrophosphate (PRPP). The other mechanism is orthosteric blocking of inhibitor binding by mutations of Gly217. Furthermore, by evaluating a panel of diverse small molecule inhibitors, we unravel inhibitor structure activity relationships on the mutant enzymes. These results provide valuable insights into the design of next generation NAMPT inhibitors that offer improved therapeutic potential by evading certain mechanisms of resistance.

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Section: Resultssupporting

confidence: 73%

Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors

Wang¹,

Elkins²,

Oh³

et al. 2014

PLoS ONE

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“…To understand the different NAMPT inhibitory activities of 3a and 3b , we analyzed their binding modes to NAMPT (PDB Code: 2GVJ [ 38 , 39 , 40 , 41 , 42 ]) by our in silico binding mode analyses using RDKit [ 48 ] and LigandScout [ 49 ]. The superimpositions of these inhibitors in the tunnel cavity revealed that they adopted almost identical chair binding forms as with the case in 1 ( Figure 4 a).…”

Section: Resultsmentioning

confidence: 99%

Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors

et al. 2020

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Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is an attractive therapeutic strategy for targeting cancer metabolism. So far, many potent NAMPT inhibitors have been developed and shown to bind to two unique tunnel-shaped cavities existing adjacent to each active site of a NAMPT homodimer. However, cytotoxicities and resistances to NAMPT inhibitors have become apparent. Therefore, there remains an urgent need to develop effective and safe NAMPT inhibitors. Thus, we designed and synthesized two close structural analogues of NAMPT inhibitors, azaindole–piperidine (3a)- and azaindole–piperazine (3b)-motif compounds, which were modified from the well-known NAMPT inhibitor FK866 (1). Notably, 3a displayed considerably stronger enzyme inhibitory activity and cellular potency than did 3b and 1. The main reason for this phenomenon was revealed to be due to apparent electronic repulsion between the replaced nitrogen atom (N1) of piperazine in 3b and the Nδ atom of His191 in NAMPT by our in silico binding mode analyses. Indeed, 3b had a lower binding affinity score than did 3a and 1, although these inhibitors took similar stable chair conformations in the tunnel region. Taken together, these observations indicate that the electrostatic enthalpy potential rather than entropy effects inside the tunnel cavity has a significant impact on the different binding affinity of 3a from that of 3b in the disparate enzymatic and cellular potencies. Thus, it is better to avoid or minimize interactions with His191 in designing further effective NAMPT inhibitors.

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“…Recently, four research groups reported their retrospective study results using large-scale numbers (297-845) of Chinese patients with a stable maintenance dose of warfarin [12,[26][27]30]. According to their results, the warfarin maintenance dose of Chinese individuals with the genotype CYP2C9*1/*1 is usually 3.0-3.69 mg/day, while patients carrying the heterozygous genotype *1/*3 required 2.13-2.74 mg/day, which is only about a 35% lower dose requirement than those with wildtype.…”

Section: Discussionmentioning

confidence: 99%