Background Drug resistance is a serious concern in the treatment

Background Drug resistance is a serious concern in the treatment of cancer. It can occur as either de novo or acquired resistance following therapy. Besides multi drug resis tance caused by ABC efflux pumps, several tar geted therapies have described the development of target specific drug resistance. Thus, up to 90% of the cases of acquired resistance to tyrosine kinase inhibitors are due to over expression of, or mutations in, the tar get kinase. Acquired resistance can be studied by inducing resistance in vitro by growing cells in the pre sence of Inhibitors,Modulators,Libraries increasing concentrations of drug. NAD is an essential cofactor in cell energy production and metabolism as well as the substrate for mono ADP ribosyltransferases, Inhibitors,Modulators,Libraries poly poly merases and sirtuins, all of these con verting NAD to nicotinamide.

PARPs are involved in DNA repair whereas sirtuins can increase cancer cell survival. To survive Inhibitors,Modulators,Libraries under stress and supply metabolites for cell growth malignant cells depend heavily on aero bic glycolysis for generation of ATP. Glycolysis requires relatively more NAD to generate ATP com pared to the oxidative phosphorylation normally occur ring in non malignant tissues. Also, cancer cells may display increased expression or activity of PARPs and sirtuins for increased DNA repair and cell survi val. The first, rate limiting step in the resynthesis path way of NAD from nicotinamide is catalyzed by nicotinamide phosphoribosyltransferase. Nicotinamide is converted to nicotinamide mononucleo tide using 5 phosphoribosyl 1 pyrophosphate and ATP as substrates. NMN is then converted to NAD by NMN adenyltransferase.

Inhibitors,Modulators,Libraries The crystal structure of NAMPT has been resolved and it has been identified as a dimer belonging to the family of type II phosphoribosyltransferases each monomer con taining two domains. The dimer contains two binding sites for nicotinamide located in the vicinity of the dimer interface and residues of both monomers may be part of Inhibitors,Modulators,Libraries the binding site. Inhibition of NAMPT leads to depletion of NAD, secondarily leading to reduction of ATP and later, cell death. Also, it leads to substrate depletion of PARPs and sirtuins and furthermore, both PARPs and sirtuins are inhibited by nicotinamide. Tumour cells are more sensitive to NAMPT inhibition and NAD depletion due to increased ATP and NAD consumption. NAMPT inhibition shows high efficacy in haemato logical malignancies in preclinical studies.

APO866 is a specific, competitive, potent inhibitor of NAMPT that displays cytotoxicity in a broad panel of cell lines. APO866 has completed a selleck MG132 phase I trial in oncology and is currently undergoing several phase II trials for advanced melanoma and cutaneous T cell lymphoma as well as a phase I II trial for refractory and relapsed B chronic lymphocytic leukaemia. CHS 828, a pyridyl cyanoguanidine, is a small molecule inhibitor displaying cytotoxicity in a broad panel of cell lines.

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