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Bruton’s tyrosine kinase (BTK) is a key protein in B cell antigen receptor (BCR) signaling pathway, and is a research hotspot in the clinical treatment of B cell tumors and B cell immune diseases. In this article, based on the structure of Ibrutinib, a series of novel irreversible BTK inhibitors with the scaffolding of 1H-pyrazolo [3, 4-d] pyrimidin-4-amine were designed and synthesized. All the compounds showed a moderate to potent inhibitory activity against BTK. Among them, compound 6b showed the best BTK kinase inhibitory activity with the IC50 value of 1.2 nM. The ADME/T properties performed by pkCSM demonstrated that compound 6b possesses a good druglikeness. Further druggability evaluation showed that 6b exhibited good water solubility and acceptable pharmacokinetic properties. Therefore, compound 6b provided a promising lead compound for developing novel irreversible BTK inhibitors.

G2/M cell cycle checkpoint protein WEE1 kinase is a promising target for inhibiting tumor growth. Although various WEE1 inhibitors have entered clinical investigations, their therapeutic efficacy and safety profile remain unsatisfactory. In this study, we employed a comprehensive virtual screening workflow, which included Schrödinger-Glide molecular docking at different precision levels, as well as the utilization of tools such as MM/GBSA and Deepdock to predict the binding affinity between targets and ligands, in order to identify potential WEE1 inhibitors. Out of ten molecules screened, 50% of these molecules exhibited strong inhibitory activity against WEE1. Among them, compounds 4 and 5 showed excellent inhibitory activity with IC50 values of 1.069 and 3.77 nM respectively, which was comparable to AZD1775. Further investigations revealed that compound 4 displayed significant anti-proliferative effects in A549, PC9, and HuH-7 cells and could also induce apoptosis and G1 phase arrest in PC9 cells. Additionally, molecular dynamics simulations unveiled the binding details of compound 4 with WEE1, notably the crucial hydrogen bond interactions formed with Cys379. In summary, this comprehensive virtual screening workflow, combined with in vitro testing and computational modeling, holds significant importance in the development of promising WEE1 inhibitors.