Research progress of mitogen-activated protein kinase interacting kinases inhibitors in tumor immunotherapy / 中国药科大学学报

@#With the rise of tumor immunotherapy, small molecule modulators targeting the immune system have become a research hotspot. As well-developed and mature targets, immunity protein kinases have attracted more and more attention. Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are located at the meeting-point of ERK and p38 MAPK signaling pathways, which can phosphorylate eukaryotic translation initiation factor 4E (eIF4E) at the conserved serine 209 exclusively and modulate the translation of mRNA. Herein we review the structural characteristics, mechanism, signaling transduction pathways and close relationship with tumors of MNKs.Meanwhile, the development process and clinical research progress of the MNKs inhibitors reported by different research institutions are introduced in detail.

Research progress in acetyl-CoA carboxylase inhibitors / 中国药科大学学报

@#Non-alcoholic fatty liver disease(NAFLD)is characterized by excessive fat deposition in hepatocytes, fat accumulates mainly in the form of triglycerides, triglycerides derive from esterification of glycerol and free fatty acids; and the synthesis of fatty acid is abnormally active in tumor cells, which is significantly higher than that of normal cells, providing necessary lipid substrates for the formation of biofilms, the production of signaling molecules and energy during the proliferation and development of tumor cells. Acetyl-CoA carboxylase(ACC)is the limiting-rate enzyme of de novo lipogenesis. And it is also an enzyme that catalyzes the first step of the fatty acid synthesis pathway; its catalyzed product, malonyl-CoA, also inhibits the oxidation of fatty acids. ACC inhibition can reduce fatty acid synthesis and promote fatty acid oxidation, which reduce the amount of fatty acids in the body. Hence, attenuating fat accumulation could improve NAFLD, and reduction of fatty acid content inhibits development of tumor tissues because lipid substrates could not satisfy the requirement of cancer cells. Therefore, ACC inhibitors have potential to be the novel drugs that can treat NAFLD and cancer. The recent research progress on ACC inhibitors is reviewed in this paper.

Advances in small molecule inhibitors of PD-1/PD-L1 immune checkpoint pathway / 中国药科大学学报

@#Studies have found that a variety of tumors continue to activate PD-1(programmed cell death protein 1, PD-1)/PD-L1(programmed cell death-ligand 1)signaling pathway by up-regulating PD-L1 expression in tumor cells and microenvironment. The dysfunction of T cells leads to the occurrence of tumor immune escape. Several PD-1/PD-L1 monoclonal antibodies have been marketed to achieve significant clinical efficacy. However, because of the high production cost, the harsh conditions for storage and transportation, and the potential immunogenicity of monoclonal antibody, the seeking for PD-1/PD-L1 small molecule inhibitors has become a hot spot in the development of new drugs. In this paper, the biological mechanisms of PD-1/PD-L1 was introduced in detail. Based on the structural classification, the research progress of PD-1/PD-L1 small molecule inhibitors was reviewed, with a prospect of the development of small molecule inhibitors.

Advances in indoleamine 2, 3-dioxygenase 1 inhibitors / 中国药科大学学报

Indoleamine 2,3-dioxygenase 1 (IDO1) is the rate-limiting enzyme which catalyses the metabolism of L-tryptophan(L-Trp) in the kynurenine pathway.It is overexpressed in many tumor cells and antigen presenting cells.This enzyme inhibits local immune response and supports tumor cells to evade immune surveillance by depleting L-Trp and producing kynurenine metabolites,thus,it is an important target for cancer immunotherapy.There are several IDO1 inhibitors with different scarfold under investigation,three of which have already entered clinical stage.The role of IDO1 in tumor immune tolerance and the research progress on IDO1 inhibitors in recent years are summarized in this paper.

Advances in antidiabetic small molecule ABHD6 inhibitors / 中国药科大学学报

Type 2 diabetes,a glucose and lipid metabolism disorder accompanied by chronic multiple organ damage,has become a huge threat to human health,α/β hydrolase domain-6 (ABHD6) regulates the insulin release negatively by hydrolyzing monoacylglycerol.Small molecule ABHD6 inhibitors have been proven to lower bloodglucose and regulates energy homeostasis,which is a potential candidate for the treatment of type 2 diabetes.This paper introduced the ABHD6 signaling pathway and its mechanism,then reviewed the progress of small molecule ABHD6 inhibitors with different structures in recent years,and analyzed the structure activity relationship.

Design, synthesis and antiplatelet evaluation of tetramethylpyrazine/chalcone hybrids / 中国药科大学学报

In order to search for new antiplatelet agents with higher potency, a series of tetramethylpyrazine ( TMP) /chalcone hybrids ( 2-26) were synthesized and evaluated based on the principle of bioisostere and hybrid-ization. They exerted inhibitory activity against adenosine diphosphate ( ADP )-induced and arachidonic acid ( AA)-induced platelet aggregation to varied extent. Among them, compound 8 was the most potent with IC50 of 0. 14 mmol/L on ADP-induced platelet aggregation ( 9. 1 folds of TMP and 10. 5 folds of chalcone ) and 0. 09 mmol/L on AA-induced platelet aggregation ( 8. 8 folds of TMP and 10. 0 folds of chalcone) , which was superior to clinically used anti-platelet drug aspirin ( ASP, IC50 =0. 15 mmol/L) .

Recent research progress in small molecule AMPK direct activators / 中国药科大学学报

@#Type 2 diabetes, an epidemic disorder characterized by high blood glucose level associated with microvascular complications, is one of the main causes of human suffer across the globe, with no effective medicine up to now. AMP-activated protein kinase(AMPK), a highly conserved serine/threonine protein kinase, is a key sensor and regulator of intracellular and whole-body energy metabolism. Small molecule AMPK direct activators have been proven to lower blood-glucose, which is a promising candidate for the treatment of type 2 diabetes. The progress on the research of small molecule AMPK direct activators in recent years is summarized in this paper.

Advances of anti-diabetic drugs based on new targets / 中国药科大学学报

@#With the deepening of research, different new anti-diabetic drug targets have been discovered and reported, several categories of anti-diabetic drugs(linagliptin, exenatide, dapagliflozin, etc. )have been brought to the market and some new drugs acting on different targets are in late-stage clinical trials. All these progresses provide new means for overcoming diabetes. GPR119, GPR120, GPR40, AMPK, apelin receptor and GSK3β are anti-diabetic targets with great research values in current days and the future. This article reviews the mechanisms, drugs and research advances with respect to the above-mentioned targets.

Advances on receptor tyrosine kinase inhibitors taking c-Met as anti-tumor target / 中国药科大学学报

@#c-Met receptor tyrosine kinase plays an important role in signaling pathways including cell proliferation, metabolism as well as tumorigenic growth, migration and angiogenesis. c-Met has emerged as an attractive target for cancer therapy. Moreover, the interactive cross-talk between c-Met signaling and several other signaling pathways underlies a key effect for resistance of anti-cancer drugs. Thus, multi-target inhibitors become a new approach to cancer therapy. This paper introduces the c-Met signaling pathway and the resistance of kinase inhibitors caused by the cross-talk between c-Met and other membrane receptors and then will reviews the progress of single-target and multi-target c-Met inhibitors.

Research progress on the function of angiotensin Ⅱ receptors in tumor / 中国药理学通报

AngiotensinⅡ is a biologically activated peptide of the rennin-angiotensin system(RAS).Beside constracting vascular and regulating blood pressure,AngⅡplays an important role in the development of tumor,inflammation and angiogenesis.The expression and major intracellular signaling pathways of AngⅡ and AngⅡ receptors in tumor are reviewed.