DYRK1B (Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1B)

Diphenhydramine was used as the internal standard...The oral bioavailability (F) was calculated to be 19.62 %. Collectively, these findings highlight compound BHBC-01's favorable pharmacokinetic and stability profiles, supporting its potential as a drug candidate for further clinical development as a multi-target anticancer agent.

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.

Key residue differences, like Phe170, Glu239 and His285 in DYRK1A, contribute to specific interactions that underpin the molecular binding pattern. By identifying conserved and isoform-specific interactions, our study provides valuable insights for the rational design of potent and selective DYRK inhibitors.

Molecular modeling suggested modes of binding interaction of selected compounds in the DYRK1A and PIM1 catalytic sites that agreed with the experimental binding data. Our results demonstrate that tricyclic isatin oximes could be potential candidates for developing anti-inflammatory drugs with neuroprotective effects for treating neurodegenerative diseases.

The membrane-permeable cysteine precursor N-acetylcysteine (NAC) can enhance the intracellular cysteine pool and thus results in decreased oxidative stress...While NAC holds therapeutic promise in alleviating treatment-associated toxicities, its application in ovarian cancer requires careful consideration based on tumour subtype, redox context, and treatment timing. Future research incorporating subtype-specific models and clinical trials will be essential to delineate the precise role of NAC and optimize its integration into ovarian cancer treatment regimens.

Similarly, Fz25 showed suitable binding parameters explored using molecular dynamic simulations in silico. These findings suggest that Fz25 warrants further preclinical and clinical investigations as a new generation of triazole congeners with significant potency in EFGR-dependent TNBC.

In summary, DYRK1B appears as a single novel key player creating a safe haven for cancer cells by acting cell-intrinsically and-extrinsically, leading to the promotion of cancer cell survival, chemoresistance, and relapse. Thus, DYRK1B appears as an attractive drug target for future therapeutic approaches.

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.

Antiproliferative activities on U87/U373 glioblastoma cell lines of the most potent compound 4k showed a moderate effect (IC50 values between 33 and 46 μM). Microsomal stabilities of the designed compounds 4a-m were also investigated, showing great disparities, depending on benzo[b]thiophene ring 5-substitution.

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.