Current Drug Targets (v.15, #6)

Lanthionine Synthetase Component C-Like Protein 2: A New Drug Target for Inflammatory Diseases and Diabetes by Pinyi Lu, Raquel Hontecillas, Casandra W. Philipson, Josep Bassaganya-Riera (565-572).
Lanthionine synthetase component C-like protein 2 (LANCL2) is a member of the LANCL protein family,which is broadly expressed throughout the body. LANCL2 is the molecular target of abscisic acid (ABA), a compoundwith insulin-sensitizing and immune modulatory actions. LANCL2 is required for membrane binding and signaling ofABA in immune cells. Direct binding of ABA to LANCL2 was predicted in silico using molecular modeling approachesand validated experimentally using ligand-binding assays and kinetic surface plasmon resonance studies. The therapeuticpotential of the LANCL2 pathway ranges from increasing cellular sensitivity to anticancer drugs, insulin-sensitizing effectsand modulating immune and inflammatory responses in the context of immune-mediated and infectious diseases. Acase for LANCL2-based drug discovery and development is also illustrated by the anti-inflammatory activity of novelLANCL2 ligands such as NSC61610 against inflammatory bowel disease and influenza-driven inflammation in mice.This review discusses the value of LANCL2 as a novel therapeutic target for the discovery and development of newclasses of orally active drugs against chronic metabolic, immune-mediated and infectious diseases.

Recent Advances in Active Hepatic Targeting Drug Delivery System by Yang Wang, Hongliang Du, Guangxi Zhai (573-599).
Hepatic diseases are turning into one of the few diseases that cannot be effectively cured due to some reasonsalthough various receptors existed in the liver. Currently, several passive targeting delivery systems have been used in thedrug/gene delivery for the treatment of hepatic diseases. For example, Zinostatin stimalamer (trade name of Smancs®), adrug-polymer conjugate, was launched in Japan in 1994, which treats hepatocellular carcinoma. More improtantly, differentmeasures would be taken in accord to the specified cell that was lesioned or dysfunctioned via interaction betweenhoming ligands and target receptors so as to improve accumulation of drugs in the target cell and to reduce nonspecifictoxicity towards other cells or organs. Therefore, it is urgent to design novel delivery systems that physically or chemicallygrafted homing devices in order to improve the targeting properties of drugs in specific cell sites.From that perspective, the present article highlights recent development of active hepatic targeting drug/gene delivery systemsfor the treatment of hepatic diseases that were mediated by some kinds of receptors including asialoglycoprotein receptors(ASGP-R), glycyrrhetinic acid receptor (GA-R), glycyrrhizin receptor (GL-R), hyaluronan receptor (HA-R) andso on.

Dipeptidyl Peptidase IV Inhibitors: A New Paradigm in Type 2 Diabetes Treatment by Sridhara Janardhan, G. Narahari Sastry (600-621).
Dipeptidyl peptidase IV (DPP4) is a promising target for the treatment of chronic metabolic type 2 diabetesmellitus (T2D). DPP4 is a highly specific serine protease involved in the regulation and cleavage of two incretin hormones,glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These incretin hormonesare released by the gastrointestinal tract in response to ingestion of food and stimulate insulin secretion and thereby regulateglucose homeostasis with a low risk of hypoglycemia and glucagon secretion. Currently different chemical classes ofDPP4 inhibitors are in last-stage of clinical trials and few of them such as sitagliptin, vildagliptin, saxagliptin alogliptinand linagliptin have already been successfully released into market. These drugs have been approved as either monotherapyor combination therapy with other oral hypoglycemic agents such as metformin, pioglitazone, sulfonylurea, glyburideand glibenclamide for the treatment of T2D. Though several clinical trial compounds were discontinued because of severeadverse toxic effects that are associated with other prolyldipeptidases include DPP8 and DPP9. The current review providesan overview of DPP4 and its inhibitors with emphasis on the structure, expression, activity, selectivity and pharmacokineticsinformation. This review further dwells upon the issues relating to the rational design and development of selectiveDPP4 inhibitors for the treatment of T2D.

Progress of HDAC Inhibitor Panobinostat in the Treatment of Cancer by Xiaoyang Li, Jian Zhang, Yuanchao Xie, Yuqi Jiang, Zhang Yingjie, Wenfang Xu (622-634).
Histone deacetylases are a class of enzymes that play important roles in post translational modifications of histonesby deacetylating the lysine residues as well as interacting with various non-histone proteins. This type of enzymes isclosely related to oncogenesis and has been proved to be attractive targets for designing novel anti-cancer agents. Over thelast 10 years, a large number of HDACs have entered pre-clinical and/or clinical trials. Among these drug candidates, thepan-HDAC inhibitor, panobinostat demonstrated high therapeutic potential as monotherapy and combined therapy in bothpreclinical models and clinical cancer patients. In this review, we have mainly focused on the recent progress of the clinicalstudies about panobinostat, and discussed its anti-cancer effects and molecular rationale for the treatment strategies.

Emerging Pathways and Promising Agents with Possible Disease Modifying Effect in Osteoarthritis Treatment by Zdravko Jotanovic, Radovan Mihelic, Branko Sestan, Zlatko Dembic (635-661).
Current modalities for osteoarthritis (OA) treatment are partially safe and effective, and only alleviate the diseasesymptomatology, but do not modify progression and structural changes of the disease. At present, there is no approvedsafe and effective disease-modifying OA drug (DMOAD) for clinical application. Therefore, there is an urgentneed for discovery of DMOAD in order to treat OA. Hopefully, the new DMOADs would also pave the way for betterunderstanding of OA pathophysiology. Given the fact that there is still no adequate remedy that will modify the course ofOA, a number of emerging pathways and promising agents with possible DMOAD effect arise targeting cartilage, synovialmembrane, and subchondral bone, or using stem cell therapy, and gene therapy. All these methodologies will be describedand discussed in this review. Available treatment methodologies for OA are unsatisfactory. In order to properlytreat OA in the future, more realistic option will be the use of multiple drugs, instead of single therapy, which is likely tobe ineffective in the treatment of such heterogeneous diseases. Which combination of drugs with DMOAD effect will besuitable for the treatment of OA, remains to be determined in future studies.