Structure-based drug design of novel carborane-containing nicotinamide phosphoribosyltransferase inhibitors

Asawa, Yasunobu; Katsuragi, Kiyotaka; Sato, Akira; Yoshimori, Atsushi; Tanuma, Sei Ichi; Nakamura, Hiroyuki

doi:10.1016/j.bmc.2019.05.013

Cited by 11 publications

(18 citation statements)

References 26 publications

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“…Many NAMPT inhibitors bind to the tunnel-shaped cavity of NAMPT ( Figure 1 ), although the role of this tunnel in NAMPT function remains unknown [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. These inhibitors have a unique pharmacophore consisting of three parts ( Figure 2 ): head (a pyridine-like aromatic moiety), linker (a tunnel-interacting moiety) and tail (a solvent-exposed bulky group).…”

Section: Resultsmentioning

confidence: 99%

“…Since the tail acts as a packing moiety against the solvent exposed tunnel exit surface, the tail structures of 3a and 3b were fixed as the same benzoyl group of 1 . The nitrogen-containing aromatic heads present in many NAMPT inhibitors mimic the natural NAM substrate of the enzyme [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. However, the head moiety of vinylpyridine ring of 1 ( Figure 2 ) is known to be able to non-specifically interact with proteins [ 43 , 44 ].…”

Section: Resultsmentioning

confidence: 99%

“…To compare the NAMPT inhibitory activities of 3a , 3b and 1 , we determined the IC 50 values by the titration curves from the standard calorimetric enzyme-cycling assay [ 31 , 36 , 37 ]. As shown in Figure 3 a, the inhibitory activity of 3a (IC 50 = 0.11 μM) was approximately 5-fold stronger than that of 1 (IC 50 = 0.52 μM).…”

Section: Resultsmentioning

confidence: 99%

“…To confirm the marked differences of anti-NAMPT activities between 3a and 3b , the anti-proliferation effects of these inhibitors on the human colon cancer cell line HCT116 were examined after continuous exposure for 72 h [ 31 , 36 , 37 ]. As shown in Figure 3 b, compound 3b displayed significantly weaker cell activity; the 50% effective concentration (EC 50 ) value was calculated to be 87.5 nM, which was approximately 200-fold higher than that of 3a (EC 50 = 0.48 nM).…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, in various types of cancer cells, NAMPT is found to be up-regulated [ 8 , 13 , 16 , 17 ], although the molecular mechanisms that dictate the salvage pathway choice remain elusive. Thus, NAMPT is considered an attractive target for the development of new anticancer drugs and therapies [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ].…”

Section: Introductionmentioning

confidence: 99%

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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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