Case Study 3
Development of ANA598 (Setrobuir) the best-in-class HCV mRNA polymerase NS5B Inhibitor via SBDD
The drug candidate ANA598 (Setrobuir), a novel HCV mRNA polymerase NS5B Inhibitor was developed using SBDD starting from a literature lead compound identified through screening. The initial starting compound had decent inhibitory activity (IC50: 30 μM). A high throughput co-crystal structure determination method was established to soak apo NS5B crystals with inhibitors. In total, over 100 different high resolution (1.5-2.5 Å) crystal structures of NS5B in complex with various candidate inhibitors were determined. Using structural information from these studies, modifications and optimization were made to the lead compound, improving inhibitory activity while avoiding DMPK and toxicity issues. The resulting compound, ANA598 (Setrobuir), was the first-in-class HCV mRNA polymerase NS5B Inhibitor targeting the palm region and entered into phase II clinical trials.
- Novel HCV NS5B polymerase inhibitors derived from 4-(1’,1’-dioxo-1’,4’-dihydro-1’l6-benzo[1’,2’,4’]thiadiazin-3’-yl)-5-hydroxy-2H-pyridazin-3-ones: Part 1. Exploration of 7’-substitution of benzothiadiazine, Bioorg. Med. Chem. Lett. 18, 1413-8.
- Structure-based design, synthesis and biological evaluation of 1,1-dioxoisothiazole and benzo[b]thiophene-1,1-dioxide derivatives as novel inhibitors of hepatitis C virus NS5B polymerase, Bioorg. Med. Chem. Lett. 18, 4181-5.
- Novel HCV NS5B polymerase inhibitors derived from 4-(1’,1’-dioxo-1’,4’-dihydro-1’l6-benzo[1’,2’,4’]thiadiazin-3’-yl)-5-hydroxy-2H-pyridazin-3-ones: Part 2. Variation of the 2- and 6-pyridazinone substituents, Bioorg. Med. Chem. Lett. 18, 1419-24.
- Pyrrolo[1,2-b]pyridazin-2-ones as potent inhibitors of HCV NS5B polymerase, Bioorg. Med. Chem. Lett 18, 3616-21.
- Novel HCV NS5B polymerase inhibitors derived from 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 5: Exploration of pyridazinones containing 6-amino-substituents), Bioorg Med Chem Lett . 18, 5635-9.
- NS5B PDB 3BSC: https://www.rcsb.org/structure/3BSC
- NS5B PDB 3GYN: https://www.rcsb.org/structure/3GYN
- NS5B PDB 3BR9: https://www.rcsb.org/structure/3BR9
- NS5B PDB 3D28: https://www.rcsb.org/structure/3D28
- NS5B PDB 3BSA: https://www.rcsb.org/structure/3BSA
Figure 1: A NS5B inhibitor bound at the
active site of NS5B