# Nicotinamide Adenine Dinucleotide (NAD) Metabolism as a Relevant Target in Cancer
## 10 NAMPT as a Therapeutic Strategy
Therefore, the coadministration of NA and NAMPT inhibitors has been proposed as a new therapeutic strategy, but only in tumours deficient in NAPRT [97; 134; 147; 137]. Moreover, it has been observed that treatment with NAMPT inhibitors combined with other drugs, such as PARP inhibitors, may be useful to improve the efficacy of the inhibitory effect and reduce toxicity [153; 154]. Therefore, the development of inhibitors with dual therapeutic targets could be a good therapeutic strategy. An example would be the compound STF-31, which is a double inhibitor of NAMPT and of the glucose transporter GLUT1. This additional inhibitory effect could be beneficial in triggering cell death in tumours with a high rate of glucose consumption. In fact, it has been observed that STF-31 is capable of selectively attacking renal carcinoma cells deficient in the von Hippel-Lindau (VHL) tumour suppressor gene [147; 156]. NAMPT-IN-3 is a double inhibitor of NAMPT and histone deacetylase (HDAC) enzymes, an enzyme family to which sirtunis belong [148]. This compound could be useful in tumours in which sirtunis act as oncogenes. NAMPT-IN-5 is a NAMPT inhibitor that also acts on CYP3A4 activity, enhancing its cytotoxic effect both in vitro and in xenograft models [149]. In addition, new NAMPT inhibitors have been conjugated with antibodies, which are called ADCs (antibody-drug conjugates), with the aim of specifically \begin{table}
\begin{tabular}{c c c c} \hline Predicted Drugs & Type & [GS] & In Video Treatments \\
**Nampt-IN-3** & Dual inhibitor of NAMPT and HDAC & 31–55 nM & 25 mg/kg by intraperitoneal injection in mice [148] \\ \hline
**Nampt-IN-5** & Dual inhibitor of NAMPT andCYP3A4 & 0.7–3.9 nM & 5–30 mg/kg oral gavage in mice [149] \\ \hline
**NAMPT inhibitor-ADC1–4** & Drug-linker conjugates for ADC (anti-c-Kit) & 0.1 pM–10 nM & 3–10 mg/kg by intraperitoneal injection in mice [150; 151] \\ \hline
**Water-soluble ruthenium** & Pro-drug photoactivated & & In skin and lung human tumour \\
**complexes** & chemotherapy (PACT) & & cell lines [152] \\ \hline
**Niraparib/Olaparib** & Combination with synergistic & & 50 mg/kg orally in mice (PARPi) [153] \\
**+NAMPT inhibitors** & effect & & \\ \hline \end{tabular}
\end{table} 
Table 2: _Cont._targeting the drug to the tumour while avoiding damage to healthy tissues. To date, the antibodies with which inhibitors have been conjugated are antibodies directed against c-kit (receptor tyrosine kinase), which acts as a proto-oncogene in many types of cancer and is involved in processes related to CSCs. Some NAMPT-ADC1-4 conjugates have shown a high efficacy in vivo, so they could be good candidates to enter clinical trials [150; 151]. Another targeted therapeutic strategy is called photoactivated chemotherapy (PACT), in which drugs are activated after irradiation with visible light in the tumour. Complexes of ruthenium with NAMPT inhibitors have been developed and have been shown to be effective in hypoxic parts of the tumour since the activation process of the prodrug is independent of oxygen concentration [152]. However, all these new NAMPT inhibitors require further preclinical study before entering clinical trials. A few years ago, the inhibitor KPT-9274/ATG-019 entered phase 1 clinical trials for patients with advanced solid tumours or [PERSON]'s lymphoma (clinicaltrials.gov, Accessed on 1 April 2022; NCT02702492). This trial evaluated the clinical efficacy of the drug in monotherapy and in combination with niacin (vitamin B3) to palliate the toxic effects and in combination with nivolumab, a monoclonal antibody directed at PD1 (programmed death receptor of T lymphocytes). Research continued in a second phase 1 trial (clinicaltrials.gov; NCT04281420) that is still recruiting patients. In late 2021, KPT-9274 entered a new phase 1 trial to evaluate its efficacy as a monotherapy in patients with relapsed or refractory acute myeloid leukaemia (clinicaltrials.gov, Accessed on 1 April 2022; NCT04914845).