# Nicotinamide Adenine Dinucleotide (NAD) Metabolism as a Relevant Target in Cancer
## 10 NAMPT as a Therapeutic Strategy
\begin{table}
\begin{tabular}{c c c c c c c} \hline \hline \multicolumn{1}{c}{Ht} & Drug & Type & Contribution & \multicolumn{1}{c}{Gifted-Frequency} & \multicolumn{1}{c}{Treatment} & \multicolumn{1}{c}{Name of the Study} \\ \hline  & & & Melanoma & NCT00432107 & Alone & Study to Assess APO866 for the Treatment of Advanced Melanoma (2006, completed) \\ \cline{3-6} II & \multirow{3}{*}{**FK866**} & Non-competitive & Cutaneous T-cell Lymphoma & \multirow{3}{*}{NCT00431912} & \multirow{3}{*}{Alone} & Study of APO866 for the Treatment of Cutaneous T-cell Lymphoma (2007, completed) \\ \cline{3-6}  & & B-cell Chronic & & & Study to Assess the Safety and Tolerance of APO866 for the Treatment of Refractory B-CLL (2007, completed) \\ \hline  & & & & & CHS 828 in Treating Patients with Solid Tumors (1999, Withdrawn) \\ \hline  & & & Relapsed or refractory lymphoma & \multirow{3}{*}{NCT03921879} & Dose escalation and expansion & Safety and Efficacy of OT-82 in Participants with Relapsed or Refractory Lymphoma (2019, recruiting) \\ \hline  & & & Solid tumors, non-Hodgkin’s lymphoma & \multirow{3}{*}{NCT02702492} & Alone or co-administered with Ministem or Niacin or Nivolumab & PAK4 and NAMPT in Patients with Solid Malignancies or Non-Hodgkin’s Lymphoma (2016, terminated) \\ \cline{3-6}  & & Competitive & & & Nixiom or Nivolumab \\ \cline{3-6} I & \multirow{3}{*}{**OPT-82**} & Oral & Solid tumors, non-Hodgkin’s lymphoma & \multirow{3}{*}{NCT04281420} & Alone or co-administered with Ministem or PAK4 and NAMPT ATG-019 in Advanced Solid Tumors or Non-Hodgkin’s Lymphoma (2020, recruiting) \\ \cline{3-6}  & & & & & KPT-9274 in Patients with Relapsed and Refractory Acute Myeloid Leukemia (2021, recruiting) \\ \hline  & & & & & \\ \end{tabular}
\end{table} 
Table 1: NAMPT inhibitors in clinical trials. However, despite the powerful antitumor effect shown by all these NAMPT inhibitors, they have not entered clinical trials because of toxicity and solubility problems due to their lipophilic chemical structures. For this reason, the strategy of incorporating polar and ionizable groups into their structures has been adopted to improve solubility. This approach, in addition to reducing toxicity, would reduce the permeability of these compounds through the cell membrane so that they could also act on the extracellular form of NAMPT (eNAMPT) [154]. GPP78 and MV78 are two analogues of FK866 that have served mainly as templates for the development of new, more soluble inhibitors [139; 141; 155]. MS0 is also an analogue of FK866 that was found to have less effective in vitro activity [145], but it served as a template for the development of better inhibitors (compounds MS1-31) [146]. LB-60-OF61, one of the latest inhibitors developed, has shown a high efficacy in cell lines that overexpress the MYC oncogene [138], which regulates and activates the expression of NAMPT and inhibits DBC1 [81], the endogenous inhibitor of SIRT1. Trans-3-(pyridin-3-yl)acrylamide-sulfonamide compounds are potent inhibitors that have shown an antiproliferative effect at subnanomolar doses in various cell lines in vitro [142]. A-1293201 and A-1307138 are two inhibitors that lack the aromatic nitrogen group mimetic to that of the natural substrate NAM. In the study, it was observed that these inhibitors maintained their antitumor effect despite not being phosphorylated by the target enzyme NAMPT, demonstrating that the formation of the phosphorylated adduct was not essential for the functionality of NAMPT inhibitors [143]. Depletion of NAD+ can be very toxic to nontumor cells, so using NAD+ precursors (e.g., nicotinic acid) as adjuvarants has been considered [63; 96]. Several studies have found that the coadministration of nicotinic acid (NA) with some NAMPT inhibitors (GMX1778, GNE617, LSN3154567, MPC-9528 and STF-31) helps prevent toxic effects, such as haematologic and retinal toxicity in rodents, while maintaining drug efficacy. However, the inhibitory effect was suppressed in NAPRT-positive tumours, that is, tumours that overexpressed this enzyme.