Overcoming PARPi resistance will provide patients with therapeutic options. The study shows, in the context of resistant disease, the potential of targeting CDC-like kinase/dual-specificity tyrosine phosphorylation-regulated kinase alone and in combination with PARP inhibitors.

We report the crystal structure of DYRK1B in complex with the small-molecule inhibitor AZ191...Moreover, detailed evaluation of the active site architecture reveals a notable difference in the accessibility of the catalytic lysine residue between DYRK1B and DYRK1A, suggesting potential strategies to distinguish selective binders. Overall, these findings provide important macromolecular insights into the DYRK1B structure and offer a structural framework to guide medicinal chemistry efforts towards improved inhibitor selectivity with minimized off-target activity.

P1, N=50, Recruiting, University of Colorado, Denver | Not yet recruiting --> Recruiting

P1, N=50, Not yet recruiting, University of Colorado, Denver

Inhibition of the Cdc2-like kinase (CLK) family by the small molecules cirtuvivint or lorecivivint results in the decreased expression of ARV7. Both inhibitors show potent anti-proliferative effects in enzalutamide-treated or -naive PC models. Thus, targeting aberrant alternative splicing at the 3'UTR of ARV7 by disturbing the CLK2/SRSF9 axis might be a valuable therapeutic approach in late stage, ARSI-resistant PC.

P1, N=30, Terminated, Biosplice Therapeutics, Inc. | Phase classification: P1b --> P1 | Active, not recruiting --> Terminated; Study was terminated due business reasons by Sponsor.

P1, N=82, Terminated, Biosplice Therapeutics, Inc. | Active, not recruiting --> Terminated; Study was terminated due business reasons by Sponsor.

Compounds 12 and 17 could also increase levels of cleaved caspase-3 and Bax, while decreasing the expression of the antiapoptotic Bcl-2 protein. These findings support the further study and development of these compounds as novel anticancer therapeutics.

Our findings confirm an important role of DYRK1A inhibitors as modulators of β-cells function and suggested a new potential target for antidiabetic therapy. Moreover, we show in detail that leucettine derivatives represent promising antidiabetic agents and are worth further evaluation, especially in vivo.