眞木 準平

Abstract Protein kinase C (PKC) is a family of serine/threonine kinases, and PKC ligands have the potential to be therapeutic seeds for cancer, Alzheimer's disease, and human immunodeficiency virus infection. However, in addition to desired therapeutic effects, most PKC ligands also exhibit undesirable pro-inflammatory effects. The discovery of new scaffolds for PKC ligands is important for developing less inflammatory PKC ligands, such as bryostatins. We previously reported that machine learning combined with our knowledge of the pharmacophore yielded 15 PKC ligand candidates, but we did not evaluate their PKC binding affinities fully. In this paper, PKC binding affinities of four candidates were examined to assess their potential as PKC ligands and to validate machine learning-assisted screening. Although compound 3′ did not bind to PKC C1 domains, 1a, 2′, and 4a exhibited moderate PKC binding affinities, suggesting that machine learning-assisted screening is advantageous in identifying new PKC ligand scaffolds.

We investigated a convergent synthesis of aplysiatoxin analogs based on a combination of ring‐closing and cross metathesis. The route provided four analogs (3a–d) with different side chains to determine the CH/π interaction with protein kinase C (PKC)‐C1 domains. Biochemical evaluation revealed that a naphthol moiety did not improve binding to PKC‐C1 domains, suggesting that the hydrogen bonding of the hydroxy group with the PKC‐C1 domains may be more important than the CH/π interaction.

Abstract 10-Methyl-aplog-1 (10MA-1), a simplified analogue of aplysiatoxin, exhibits a high binding affinity for protein kinase C (PKC) isozymes with minimal tumor-promoting and proinflammatory activities. A recent study suggests that 10MA-1 could reactivate latent human immunodeficiency virus (HIV) in vitro for HIV eradication strategy. However, further in vivo studies were abandoned by a dose limit caused by the minimal water solubility of 10MA-1. To overcome this problem, we synthesized a phosphate ester of 10MA-1, 18-O-phospho-10-methyl-aplog-1 (phos-10MA-1) to improve water solubility for in vivo studies. The solubility, PKC binding affinity, and biological activity of phos-10MA-1 were examined in vitro, and the biological activity was comparable with 10MA-1. The pharmacokinetics studies in vivo were also examined and suggest that further optimization for improving metabolic stability is required in the future.

We have designed and synthesized a new PKC ligand with a novel skeleton based on alotaketals through in silico screening, docking analysis, and molecular dynamics simulation. The new ligand has a higher affinity for PKCα-C1A than for PKCδ-C1B.