AS3288802, a highly selective antibody to active plasminogen activator inhibitor-1 (PAI-1), exhibits long efficacy duration in cynomolgus monkeys.

Antibodies have strong affinity to their target molecules, a characteristic that is utilized in antibody drugs. For antibody drugs, target molecule specificity and long duration pharmacokinetics, along with strong affinity to the target molecule are important characteristics. Plasminogen activator inhibitor-1 (PAI-1) is one of the key regulators of the fibrinolysis system, and the benefits of PAI-1 activity inhibition have been widely reported for multiple thrombosis and fibrosis-related diseases. Here, we generated a novel antibody, AS3288802, with high selectivity for active PAI-1. AS3288802 exhibited prolonged and strong inhibition of PAI-1 activity in cynomolgus monkey blood in vivo. Given that AS3288802 showed prolonged antigen inhibition activity due to its high target molecule selectivity, we propose that increasing target molecule selectivity may be a key strategy for lengthening the efficacy duration of antibody drugs. AS3288802 may be a promising anti-PAI-1 antibody drug with multiple clinical applications including thrombosis and fibrosis-related diseases.

Discovery of a novel nicotinamide phosphoribosyl transferase (NAMPT) inhibitor via in silico screening.

Nicotinamide phosphoribosyl transferase (NAMPT) is a key enzyme in the salvage pathway of mammalian nicotinamide adenine dinucleotide (NAD) biosynthesis, catalyzing the synthesis of nicotinamide mononucleotide from nicotinamide (Nam). The diverse functions of NAD suggest that NAMPT inhibitors are potential drug candidates as anticancer agents, immunomodulators, or other agents. However, difficulty in conducting high-throughput NAMPT assay with good sensitivity has hampered the discovery of novel anti-NAMPT drugs with improved profiles. We combined an in silico screening strategy with a radioisotope (RI)-based enzyme assay and rationally identified promising NAMPT inhibitors with novel structures. AS1604498 was the most potent inhibitor, with an IC50 of 44 nM, and inhibited THP-1 and K562 cell line growth with the IC50 of 198 nM and 673 nM, respectively. The mode of action was found to reduce intracellular NAD following apoptosis, suggesting that these compounds inhibit NAMPT in cell-based assay. This strategy can be used to discover new drug candidates with targets which are difficult to assess through high-throughput screening. Our hit compounds may be used as seed compounds for developing new therapeutics with NAMPT.