Small molecules targeting the innate immune cGAS‒STING‒TBK1 signaling pathway

Multiple cancer immunotherapies including chimeric antigen receptor T cell and immune checkpoint inhibitors (ICIs) have been successfully developed to treat various cancers by motivating the adaptive anti-tumor immunity. Particularly, the checkpoint blockade approach has achieved great clinic success as evidenced by several U.S. Food and Drug Administration (FDA)-approved anti-programmed death receptor 1/ligand 1 or anti-cytotoxic T lymphocyte associated protein 4 antibodies. However, the majority of cancers have low clinical response rates to these ICIs due to poor tumor immunogenicity. Indeed, the cyclic guanosine monophosphate-adenosine monophosphate synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS‒STING‒TBK1) axis is now appreciated as the major signaling pathway in innate immune response across different species. Aberrant signaling of this pathway has been closely linked to multiple diseases, including auto-inflammation, virus infection and cancers. In this perspective, we provide an updated review on the latest progress on the development of small molecule modulators targeting the cGAS‒STING‒TBK1 signaling pathway and their preclinical and clinical use as a new immune stimulatory therapy. Meanwhile, highlights on the clinical candidates, limitations and challenges, as well as future directions in this field are also discussed. Further, small molecule inhibitors targeting this signaling axis and their potential therapeutic use for various indications are discussed as well.

Alectinib: a novel second generation anaplastic lymphoma kinase (ALK) inhibitor for overcoming clinically-acquired resistance

The development of inhibitors for the tyrosine anaplastic lymphoma kinase (ALK) has advanced rapidly, driven by biology and medicinal chemistry. The first generation ALK inhibitor crizotinib was granted US FDA approval with only four years of preclinical and clinical testing. Although this drug offers significant clinical benefit to the ALK-positive patients, resistance has been developed through a variety of mechanisms. In addition to ceritinib, alectinib is another second-generation ALK inhibitor launched in 2014 in Japan. This drug has a unique chemical structure bearing a 5H-benzo[b]carbazol-11(6H)-one structural scaffold with an IC50 value of 1.9 nmol/L, and is highly potent against ALK bearing the gatekeeper mutation L1196M with an IC50 of 1.56 nmol/L. In the clinic, alectinib is highly efficacious in treatment of ALK-positive non-small cell lung cancer (NSCLC), and retains potency to combat crizotinib-resistant ALK mutations L1196M, F1174L, R1275Q and C1156Y.

Purification of patchouli alcohol in volatile oil of Pogostemon cablin by molecular distillation / 中草药

Objective The volatile oil was further purified to get the patchouli alcohol by molecular distillation taking patchouli oil which contained 23.97% of patchouli alcohol as raw material.Methods The best process parameters,including temperature,feed rate,and scraping rate,of molecular distillation technique for separating patchouli oil were studied by orthogonal test.The content was detected by GC under the conditions of elastic quartz capillary column HP-5,detector temperature 280 ℃,gasification temperature 280 ℃,distributary refer 20∶1.The effects of evaporation temperature on content and extraction rate of the patchouli oil had been investigated and the difference between the molecular and vapor distillations was studied.Results Content and extraction rate of patchouli alcohol under the best evaporation temperature 65 ℃ by molecular distillation reached to 40.71% and 76.55%,respectively.Conclusion The molecular distillation technique that could get the product with higher purity and extracting rate than that by vapor distillation in patchouli oil purification has a very good prospect in industry.