In vitro drug release experiments demonstrated that AZ191 exhibited rapid release within the first three hours with a cumulative release of approximately 26%, whereas cisplatin showed minimal early release (∼5%) followed by a markedly accelerated release. In vitro antitumor studies confirmed that the combined chemo-hyperthermia treatment using the core-shell MSs produced the most effective inhibitory effect on drug-resistant OC cells, reducing cell viability to 21% after 48 h, significantly outperforming either chemotherapy or hyperthermia alone. This strategy enables a "resistance-reversal first, precision-killing later" treatment model, offering a novel and effective solution for the treatment of drug-resistant OC.

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.

The present data identify DYRK1B as a regulator of phenotypic plasticity in A549 cells. Increased expression of DYRK1B induces mesenchymal traits in A549 lung adenocarcinoma cells.

Consistently, AURK inhibitors VX-680 (tozasertib), MLN8237 (alisertib), AZD1152-HQPA (barasertib) resulted in the upregulation of DYRK1B expression in A549 cells. In summary, our findings indicate that the expression of DYRK1A and DYRK1B is differentially regulated in cancer cells and reveal that the kinase inhibitor XMU-MP-1 increases DYRK1B expression likely through off target inhibition of Aurora kinases.

Compared to competitive kinase inhibition, targeted degradation of DYRK1 by DYR684 provided improved suppression of downstream signaling. Collectively, our results identify DYRKs as viable targets for PROTAC-mediated degradation and qualify DYR684 as a useful chemical probe for DYRK1A and DYRK1B.

In light of DYRK inhibitors currently entering clinical phase testing, our data thus provide a novel and clinically translatable approach targeting both the cancer cell compartment and its microenvironment.

In this review, apart from summarizing the data establishing Dyrk1B as a therapeutic target in cancer, we highlight the most potent Mirk/Dyrk1B inhibitors recently reported. We also discuss the limitations and perspectives for the structure-based design of Mirk/Dyrk1B potent and highly selective inhibitors based on the accumulated structural data of Dyrk1A and the recent crystal structure of Dyrk1B with AZ191 inhibitor.

Combined treatment with the DYRK1B inhibitor AZ191 and IR resulted in (supra-) additive tumor cell killing in colorectal tumor cell systems and in primary CRC organoids. Mechanistic investigations support the rational to target the stress-enhanced survival kinase DYRK1B in combination with irradiation to overcome hypoxia- and starvation-induced treatment resistances.

Additionally, molecular dynamic simulations were performed and found that MMA307 and MMA320 have higher binding affinities than sorafenib in MEK, BRAF, cyclin D , and Dyrk1B (dual-specificity tyrosine phosphorylation-regulated kinase 1B). To conclude, the present study is the first to report on the antiproliferative potential of novel estrone analogs and provide evidence that MMA307 and MMA320 are promising novel lead candidates for the development of anti-lung cancer drugs.

In contrast, the cellular SAR highlights correlations between inhibition of specific kinase targets and some but not all cellular effects. Leucettines deserve further development as potential therapeutics against various diseases on the basis of their molecular targets and cellular effects.

In vivo, DYRK1A/B inhibition-induced tumour stasis in a U87MG tumour xenograft model. These results suggest that further evaluation of VER-239353 as a treatment for glioblastoma is therefore warranted.