Novel Efficient Multistage Lead Optimization Pipeline Experimentally Validated for DYRK1B Selective Inhibitors

Abstract

In addition to general challenges in drug discovery such as the identification of lead compounds in time- and cost-effective ways, specific challenges also exist. Particularly, it is necessary to develop pharmacological inhibitors that effectively discriminate between closely related molecular targets. DYRK1B kinase is considered a valuable target for cancer-specific mono- or combination chemotherapy; however, the inhibition of its closely related DYRK1A kinase is not beneficial. Existing inhibitors target both kinases with essentially the same efficiency, and the unavailability of the DYRK1B crystal structure makes the discovery of DYRK1B-specific inhibitors even more challenging. Here, we propose a novel multi-stage compound discovery pipeline aimed at in silico identification of both potent and selective small molecules from a large set of initial candidates. The method uses structure-based docking and ligand-based quantitative structure–activity relationship modeling. This approach allowed us to identify lead and runner-up small-molecule compounds targeting DYRK1B with high efficiency and specificity.

Structural perspective on the design of selective DYRK1B inhibitors

“…Alexandrov and colleagues have recently reported an inventive pipeline for optimization of DYRK1B selective inhibitors (Alexandrov et al, 2022). However, the major obstacle for this and other structure based design methods was that experimental structure of DYRK1B was not available.…”

“…Alexandrov et al ( 7 ) reported a pipeline for optimizing selective inhibitors for DYRK1B. However, the key challenge in this and other structure-based design approaches was the lack of the experimental structure for DYRK1B.…”

“…This result demonstrates that a concentration of 10 μM AZ191 is sufficient to inhibit DYRK1B activity and thereby restore the functionality of the calcineurin/NFAT pathway in our cellular model. Alexandrov et al (7) reported a pipeline for optimizing selective inhibitors for DYRK1B. However, the key challenge in this and other structure-based design approaches was the lack of the experimental structure for DYRK1B.…”

“…To allow investigation of specific effects of each paralogue inhibition selective inhibitors are needed. For example, it has been suggested that selective inhibition may be beneficial in certain types of cancer (Alexandrov et al, 2022; Hu et al, 2013). Inhibitor development for closely related molecular targets is challenging and absence of crystal structure of DYRK1B further complicates the effort.…”

“…To understand the specific effects of inhibiting each paralogue, selective inhibitors are needed. These selective inhibitors would also play a key role in the treatment of certain types of cancer ( 7 , 30 ). However, developing selective inhibitors for closely related molecular targets is challenging and the lack of a crystal structure of DYRK1B further complicates the effort.…”