HCK (HCK Proto-Oncogene)

Building on our previously developed dual HCK/BTK inhibitor KIN-8194, we designed DFCI-002-06, a first-in-class proteolysis-targeting chimera (PROTAC) that potently and selectively degrades both kinases while retaining kinase inhibitory activity with improved selectivity versus KIN-8194. DFCI-002-06 induced enhanced apoptosis in MYD88Mut lymphoma cells and remained active against ibrutinib-resistant BTKCys481 variants...Preclinical safety studies showed a favorable profile, including a negative Ames test, no hERG inhibition at relevant concentrations, and excellent tolerability in a 21 day rat toxicity study. DFCI-002-06 represents a rational dual-target degradation strategy for MYD88Mut lymphomas.

This metabolic shift repolarized TAMs to the M1 phenotype, resulting in a decrease in IL-10 secretion, which enhanced the immune response of anti-tumor CD8+ T cells and increased the sensitivity of TNBC to immune checkpoint blockade therapy. This project uncovers a previously unrecognized anti-tumor mechanism of DCC-2036, and proposes a combination strategy that utilizes DCC-2036 alongside immune checkpoint inhibitors to improve TNBC immunotherapy.

From cell lines-based functional assays to bioinformatic analysis, this study demonstrated that clinical potential of ARHGAP6 as a novel biomarker of AML.

Furthermore, there were notable variations in the quantity of different immune categories of cells between the groups with high and low FGR expression. By targeting FGR, miR-378a-5p prevents LUAD cell invasion, migration and proliferation.

These agents should be rationally integrated into precision medicine combination therapies informed by genetic, epigenetic, and posttranscriptional insights that will be essential to refine risk stratification and minimize the risk of resistance. Novel strategies leveraging artificial intelligence and machine learning could accelerate discovery and optimize treatment frameworks.

This study highlights the therapeutic potential of minor cannabinoids and identifies their potential novel protein targets. Moreover, we demonstrate the utility of inverse molecular docking fingerprinting with clustering to identify compounds with similar binding patterns as well as identify pharmacophore-related compounds in a structurally agnostic manner, paving the way for future drug discovery and development.

This study suggests that curcumenol inhibits IgE-mediated allergic reactions by suppressing the activation Lyn and Fyn Src family kinases in OVA-challenged model animals. Therefore, curcumenol could be used as an effective alternative therapeutic for allergic diseases.

Our findings reveal numerous plasma proteins linked to metabolic-related diseases. These findings offer fresh insights into the etiology, diagnostics, and treatment of these conditions.

Computational analyses identified residues in the putative interaction interface between NLRP12 and HCK, suggesting that HCK likely binds NLRP12 in the region between its NACHT domain and pyrin domain (PYD); removal of the NLRP12 PYD abrogated this interaction in vitro. Overall, our work identifies HCK as a regulator of NLRP12-mediated PANoptosis, suggesting that it may serve as a potential therapeutic target for mitigating inflammation and pathology.

The common genes that were upregulated at pH 6.0, pH 6.5, and pH 7.0 were lymphocyte cell-specific protein-tyrosine kinase (LCK) [pH 6.0, FC: 2.93; pH 6.5, FC: 2.93; pH 7.0, FC: 3.32], FGR proto-oncogene, Src family tyrosine kinase (FGR) [pH 6.0, FC: 4.17; pH 6.5, FC: 5.25; pH 7.0, FC: 5.09], and ArfGAP With SH3 domain, ankyrin repeat, and PH domain 3 (ASAP3) [pH 6.0, FC: 2.37; pH 6.5, FC: 3.84; pH 7.0, FC: 2.51]. The acidic environment triggers the activation of proto-oncogenes, which may trigger tumor initiation in chronic pancreatitis.

Collectively, these findings indicate that DCC-2036 promotes autophagy in osteosarcoma (OS) cells by targeting the HCK/AKT/mTORC1 axis and exerts anti-tumor effects without significant toxicity. Consequently, DCC-2036 emerges as a promising therapeutic agent for the treatment of HCK-overexpressing osteosarcoma.

Finally, a total of 16 hub genes were identified by CytoHubba and MCODE plugins in Cytoscape, including Chemokine (C-C motif) ligand 4(CCL4), Toll-like receptor 2 (TLR2), Integrin Beta 2(ITGB2), Chemokine (C-C motif) Receptor 1(CCR1), Toll-Like Receptor 8 (TLR8), Fc Fragment of IgG Receptor IIa (FCGR2A), Neutrophil Cytosolic Factor 2(NCF2), Leukocyte immunoglobulin-like receptor B2(LILRB2), FGR proto-oncogene, Src family tyrosine kinase(FGR), Intercellular Adhesion Molecule 1 (ICAM1), Caspase 1(CASP1), Matrix Metallopeptidase 9(MMP9), Cluster of Differentiation 163(CD163), Complement Component 5a Receptor 1 (C5AR1), Neutrophil Cytosolic Factor 4 (NCF4), Selectin P (SELP). This study discovered a link between UC and AA, as well as shared hub genes and pathways, which may bring new insights into the processes of UC and AA.