Virtual Screening to Successfully Identify Novel Janus Kinase 3 Inhibitors: A Sequential Focused Screening Approach

Abstract

In an effort to identify novel Janus kinase 3 inhibitors, a sequential focused screening approach was adopted to search our in-house chemical database. By biologically testing only 79 selected compounds, we successfully identified 19 compounds showing IC 50 < 20 microM, with four of them in the nanomolar range. Particularly, a 3,5-disubstituted pyrazolo[4,3- d]pyrimidine scaffold emerged as a promising candidate for further lead optimization. With the advantages of efficiency and flexibility, this approach may be utilized to identify leads for other therapeutic targets.

Data-driven approaches used for compound library design, hit triage and bioactivity modeling in high-throughput screening

“…The low cost and resources required for vHTS combined with the introduction of large public bioactivity databases [ 11 ] facilitate its application to many drug discovery campaigns. This has resulted in numerous success stories: the discovery of inhibitors/ligands of DNA methyltransferases (DNMTs) [ 81 , 82 ], kinases [ 83 , 84 ], GPCRs [ 85 , 86 ] and other relevant targets ( Table 2 ) [ 87 , 88 ]. Nevertheless, the success of vHTS depends on initial data quality and validation procedures.…”

High Throughput Screening Approach to Lead Discovery

“…In total, only 79 out of the 1 million compounds in the corporate compound collection were screened. Interestingly, the most potent hit from this sequential screen was not picked up in a subsequent HTS campaign [105].…”

Discovery of Novel Tricyclic Thiazepine Derivatives as Anti-Drug-Resistant Cancer Agents by Combining Diversity-Oriented Synthesis and Converging Screening Approach

“…This approach has demonstrated its efficiency and flexibility in several lead identification projects. 11 …”

“…Converging screening conducts screening in an iterative fashion instead of attempting to find all the desirable hits in a single round of screening. This approach has demonstrated its efficiency and flexibility in several lead identification projects …”