Discovery of orally active 1,4,5,6,8-pentaazaacenaphthylens as novel, selective, and potent covalent BTK inhibitors for the treatment of rheumatoid arthritis.

Bruton's tyrosine kinase (BTK) plays a crucial role in adaptive and immune responses by modulating B-cell, Fc, toll-like, and chemokine receptor signaling pathways. BTK inhibition is a promising therapeutic approach for the treatment of inflammatory and autoimmune diseases. The development of novel, highly selective, and less toxic BTK inhibitors may be beneficial for the treatment of autoimmune diseases with unmet medical needs. In this study, structure-based drug design was used to discover a series of novel, potent, and selective covalent BTK inhibitors with a 1,4,5,6,8-pentaazaacenaphthylen scaffold. Among them, compound 36R exhibited high kinase selectivity, long target occupancy time, appropriate pharmacokinetic properties, and dose-dependent efficacy in a rat model of collagen-induced arthritis. Therefore, 36R is a novel BTK inhibitor requiring further development for the treatment of autoimmune diseases.

Effective Reaction-Based De Novo Strategy for Kinase Targets: A Case Study on MERTK Inhibitors.

Reaction-based de novo design is the computational generation of novel molecular structures by linking building blocks using reaction vectors derived from chemistry knowledge. In this work, we first adopted a recurrent neural network (RNN) model to generate three groups of building blocks with different functional groups and then constructed an in silico target-focused combinatorial library based on chemical reaction rules. Mer tyrosine kinase (MERTK) was used as a study case. Combined with a scaffold enrichment analysis, 15 novel MERTK inhibitors covering four scaffolds were achieved. Among them, compound 5a obtained an IC50 value of 53.4 nM against MERTK without any further optimization. The efficiency of hit identification could be significantly improved by shrinking the compound library with the fragment iterative optimization strategy and enriching the dominant scaffold in the hinge region. We hope that this strategy can provide new insights for accelerating the drug discovery process.

Design and synthesis of 1H-indazole-3-carboxamide derivatives as potent and selective PAK1 inhibitors with anti-tumour migration and invasion activities.

Aberrant activation of p21-activated kinase 1 (PAK1) is associated with tumour progression, and PAK1 has been recognized as a promising target for anticancer drug discovery. However, the development of potent PAK1 inhibitors with satisfactory kinase selectivity and favourable physicochemical properties remains a daunting challenge. Herein, we identified the 1H-indazole-3-carboxamide derivatives as potential PAK1 inhibitors using a fragment-based screening approach. The representative compound 30l exhibited excellent enzyme inhibition (PAK1 IC50 = 9.8 nM) and high PAK1 selectivity toward a panel of 29 kinases. The Structure-activity relationship (SAR) analysis showed that substituting of an appropriate hydrophobic ring in the deep back pocket and introducing a hydrophilic group in the bulk solvent region were critical for PAK1 inhibitory activity and selectivity. Additionally, the hERG channel activity of 30l demonstrated its low risk of hERG toxicity. Furthermore, it significantly suppressed the migration and invasion of MDA-MB-231 cells by downregulating Snail expression without affecting the tumour growth. These results provide a new type of chemical scaffolds targeting PAK1 and suggested that 1H-indazole-3-carboxamide derivatives may serve as lead compounds for the development of potential and selective PAK1 inhibitors.