WRN (WRN RecQ Like Helicase)

It also demonstrated favorable preclinical pharmacokinetic properties with superior plasma stability and exposure compared with VVD-214. Furthermore, compound 22 showed statistically significant antitumor activity in the HCT116 xenograft mouse model with clear dose dependence.

The Werner Syndrome RecQ DNA helicase (WRN) plays a crucial role in DNA metabolism and genome stability. This patent collectively demonstrates the synthesis, composition and formulation about novel WRN inhibitors featuring bicyclic heterocycles for cancer treatment.

These findings suggest a novel role for ZEB1 in promoting ALT both transcriptionally and post-transcriptionally at multiple levels.

In this study, we characterized resistance mechanisms using the clinical candidate HRO761 and two novel inhibitors in MSI cell lines and xenograft models...This chemotype-specific resistance profile suggests opportunities for developing next-generation inhibitors that retain activity against resistant variants and for implementing rational treatment strategies with existing inhibitors. Overall, our findings demonstrate that on-target resistance to WRN inhibitors emerges rapidly in dMMR backgrounds but also highlight potential approaches to overcome resistance, supporting continued development of WRN-targeted therapies for MSI cancers.

Biochemical and biophysical data demonstrate how nucleotide and inhibitor binding remodel these conformations and suggest that known clinical inhibitors (HRO761 and VVD-133214) function by locking WRN in inactive, 'off-DNA' states. Resistance emerged rapidly in vitro, through acquired point mutations as well as altered WRN expression. Together, our findings provide a structural framework for the WRN structural cycle and support the development of next-generation 'on-DNA' inhibitors to overcome resistance.

Our report confirms the previously reported association of the biallelic CIDEC variant with the FPL phenotype and also highlights the extremely rare possibility of co-occurrence of FPLD5 with thyroid cancer, a clinical feature of Werner syndrome. Thus, our patient may not only need surveillance for the metabolic complications of FPLD5, such as diabetes, hypertriglyceridemia, and hepatic steatosis, but also for WRN-associated neoplasms and features of premature aging.

Filling these conceptual and informational gaps will allow better prediction of tissue-specific adverse effects of WRN helicase inhibition or WRN loss. We highlight important, unanswered questions in WRN biology and newly emerging research and translational opportunities.

During the fragment optimization process, structures of WRN with key prioritized fragments reveal multiple conformations of WRN with significant domain rotations up to 180°, including a WRN conformation not previously described. Rooted in a combination of biochemical, biophysical, and structural approaches, we present the detailed analyses of optimized chemical matter evolved from screening hits and the unique ability of WRN to accommodate diverse conformations as detailed by structural characterization.

By comparing the cellular responses to pyridostatin and hydroxyurea, respectively, we confirmed that p53S specifically regulates G4-related DNA replication stress...Together, our data indicate that certain tumorigenic features can be applied to balance with premature aging, rescuing the aging phenotype without tumor risk. This study suggests a new mechanism in aging regulation and provides the possibility of developing a tumor-free longevity strategy and targeting G4 and DNA replication in aging-related tumor therapy.

Furthermore, the proposed DKWRN model demonstrated notable enhancements in classification accuracy when compared to existing techniques. Specifically, its performance exceeded that of Bayesian-based optimized convolutional neural network (CNN) for ALL detection (BO-ALLCNN) by 5.91 %, Support vector machine (SVM) by 4.63 %, ResNet-18 combined with SVM by 4.04 %, Residual Convolutional Neural Network (ResNet-152) by 2.27 %, DKN by 1.51 %, and WRN by 0.55 %, respectively.

The challenges that must be addressed to see the true potential of these agents are discussed. Finally, we consider future directions and the necessity for integration of biomarkers and genomic profiling in DDR inhibitor clinical trials to optimally identify patients with tumours genetically vulnerable, and so crucially, take advantage of the selective therapeutic opportunity provided by DDR inhibition.

Impact statement BRCA2, MRE11-RAD50, and WRN-DNA2 encode human proteins that process replication forks and result in distinct genetic instabilities and cancers when mutated. Here, we show their bacterial homologs act on unique replication fork substrates-those at DNA damage sites or as replication completes, and discuss their possible functional conservation in humans.