STK17A (Serine/Threonine Kinase 17a)

Small molecule inhibitors for STK17A, including those specifically developed for STK17A and those designed for other kinases but also inhibit STK17A as an unintended target, are discussed. Finally, some outlooks for drug discovery regarding STK17A are described.

Despite these advances, challenges such as drug resistance, off-target effects, and toxicity persist. Future research will focus on optimizing synthetic approaches, improving drug selectivity, and enhancing bioavailability to increase clinical efficacy.

In summary, we successfully identified and optimized STK17B kinase inhibitors which led to increased T cell responses in vitro and in vivo. This allowed us to evaluate the potential of STK17B inhibition as an approach for cancer immunotherapy.

Based on profiling studies against two wild-type kinase panels (375 and 398 kinases, respectively), compound 9 had strong inhibition of both STK17A and STK17B but moderate off-target inhibition only for AAK1, MYLK4, and NEK3/5. In addition, compound 9 had good oral bioavailability, paving the way for in vivo studies against various cancers.

The DNAm levels at three individual CG dinucleotides (CpG sites) in the genes MYO1D, STK17A, and SP140 correlated with CD34 cell numbers in mobilized peripheral blood and with blast counts in leukemia. In the future, such epigenetic biomarkers can support the evaluation of stem cell mobilization, HSPC harvesting, or blast count in leukemia.

Furthermore, the per-residue free energy decomposition unveiled that the energy contribution from Arg41 at the phosphate-binding loop of STK17B was the determinant factor responsible for the binding specificity of PKIS43. This study may provide useful information for the rational design of novel and potent selective inhibitors toward STK17B.

A commentary is provided on the potential importance of DAPK3 in facilitating epithelial restitution and wound healing during the resolution of colitis. An update on efforts to develop selective pharmacologic effectors of individual DAPK members is also supplied.

Crystal structures demonstrated that CK156 (34) acts as a type I inhibitor. However, contrary to studies using genetic knockdown of DRAK1, we have seen the inhibition of cell growth of glioma cells in 2D and 3D culture only at low micromolar concentrations.

We found that DRAK1 protein was destabilized through K48-linked polyubiquitination promoted by the Cullin scaffold protein 3 (CUL3) / speckle-type POZ (poxvirus and zinc finger protein) protein (SPOP) E3 ubiquitin ligase in paclitaxel-resistant cells. Collectively, these findings suggest that DRAK1 may serve as a potential predictive biomarker for overcoming paclitaxel resistance in cervical cancer.