Repositioning of Montelukast to inhibit proliferation of mutated KRAS pancreatic cancer through a novel mechanism that interfere the binding between KRAS and GTP/GDP.

Pancreatic cancer is one of the most lethal cancer types with 5-year survival rate of ∼10.8%. Various KRAS mutations exist in ∼85% pancreatic cancer cell lines. Mutated KRAS is a major cause that leads cancer cell proliferation. Chemotherapy is still the major treatment for pancreatic cancer. Alternatively, repositioning old drug to inhibit mutated KRAS may be a cost-effective way for pancreatic cancer treatment. In this study, we choose mutated KRAS (G12D) as a target. Based on mutated KRAS GTP binding domain (hydrolyze GTP to GDP), we perform virtual screening on FDA-approved drugs. Montelukast shows strong binding affinity to mutated KRAS as well as interfering both GTP and GDP binding to mutated KRAS. Furthermore, Montelukast shows very strong anti-proliferation effect on mutated KRAS pancreatic cancer cells both in vitro and in vivo. Our results support repositioning of Montelukast as single agent for pancreatic cancer treatment.

Repositioning Lomitapide to block ZDHHC5-dependant palmitoylation on SSTR5 leads to anti-proliferation effect in preclinical pancreatic cancer models.

Palmitoylation of proteins plays important roles in various physiological processes, such as cell proliferation, inflammation, cell differentiation etc. However, inhibition of protein palmitoylation has led to few new drugs to date. ZDHHC5 serves as a key enzyme to catalyze palmitoylation on SSTR5 (a proven anti-proliferation receptor in pancreatic cells). Herein, we compare single-cell transcriptome data between pancreatic cancer tissues and normal pancreas tissues and identify that ZDHHC5 is a potential target to inhibit proliferation of pancreatic cancer cells. In addition, we report the repositioning of an orphan drug (Lomitapide) as an inhibitor of ZDHHC5, and we speculate that this inhibitor may be able to block palmitylation on SSTR5. Pharmacological blockade of ZDHHC5 with Lomitapide results in attenuated cancer cell growth and proliferation which collectively contributes to antitumor responses in vitro and in vivo. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of ZDHHC5 in pancreatic cancer, representing a new class of palmitoylation targeted therapy and laying a framework for paradigm-shifting therapies targeting cancer cell palmitoylation.

Magnetic Co-based carbon materials derived from core-shell metal-organic frameworks for organic contaminant elimination with peroxymonosulfates.

The exploitation of highly efficient and reusable catalysts based on peroxymonosulfate (PMS) activation has attracted considerable attention in the environmental catalysis field. Herein, Co-doped graphitic carbon (Co-GC) on nitrogen-doped carbon (NC@Co-GC) was constructed and first employed as an efficient heterogeneous catalyst to activate PMS for the removal of organic contaminants. Coupled with only 0.5 mM PMS, NC@Co-GC could achieve 96.7% removal of reactive brilliant red within 14 min. Most importantly, the rate constant of NC@Co-GC was 7 times higher than that of commercial Co3O4. Additionally, NC@Co-GC with PMS could also exhibit high elimination rates of other dyes and organic contaminants including 8-hydroxy-quinoline, ciprofloxacin and phenol for the same condition. Benefiting from the magnetic properties, the catalyst could be separated and recycled by a magnet. Through the combination of the electron paramagnetic resonance (EPR) technology and the radical quenching experiments, it could be concluded that four types of ROS including 1O2, SO4˙-, ˙OH and O2˙- were involved and 1O2 played a dominant role in 3BF elimination. Interestingly, the catalytic efficiency remarkably improved and the rate constant increased by 3-fold in the presence of Cl-, which always played a negative role and functioned as a ROS scavenger in a previous study. This report will inspire new studies for the development of a Co-based catalyst with both high efficiency and extraordinary reusability.