Over 2 decades ago, the proteasome was considered a risky or even untenable therapeutic target. Today, proteasome inhibitors are a mainstay in the treatment of multiple myeloma (MM) and have sales in excess of 3 billion US dollars annually. More importantly, the availability of proteasome inhibitors has greatly improved the survival and quality of life for patients with MM. Despite the remarkable success of proteasome inhibitor therapies to date, the potential for improvement remains, and the development and optimal use of proteasome inhibitors as anticancer agents continues to be an active area of research. In this review, we briefly discuss the features and limitations of the 3 proteasome inhibitor drugs currently used in the clinic and provide an update on current efforts to develop next-generation proteasome inhibitors with the potential to overcome the limitations of existing proteasome inhibitor drugs.

Current nanoparticle (NP) drug carriers mostly depend on the the enhanced permeability and retention (EPR) effect for selective drug delivery to solid tumors. However, in the absence of persistent EPR effect, the peritumoral endothelium can function as an access barrier to tumors and negatively affect the effectiveness of NPs. In recognition of the peritumoral endothelium as a potential barrier in drug delivery to tumors, poly(lactic-co-glycolic acid) NPs are modified with a quinic acid (QA) derivative, synthetic mimic of selectin ligands. QA-decorated NPs (QA-NP) interact with human umbilical vein endothelial cells (HUVECs) expressing E-/P-selectins and induce transient increase in endothelial permeability to translocate across the layer. QA-NP reach selectin-upregulated tumors, achieving greater tumor accumulation and paclitaxel (PTX) delivery than polyethylene glycol-decorated NPs (PEG-NP). PTX-loaded QA-NP show greater anti-cancer efficacy than Taxol® or PTX-loaded PEG-NP at the equivalent PTX dose in different animal models and dosing regimens. Repeated dosing of PTX-loaded QA-NP for two weeks result in complete tumor remission in 40-60% of MDA-MB-231 tumor-bearing mice, while those receiving control treatments succumb to death. QA-NP can exploit the interaction with selectin-expressing peritumoral endothelium and deliver anti-cancer drugs to tumors to a greater extent than the level currently possible with the EPR effect.

Carfilzomib (CFZ) is the second-in-class proteasome inhibitor with much improved efficacy and safety profiles over bortezomib in multiple myeloma patients. In expanding the utility of CFZ to solid cancer therapy, the poor aqueous solubility and in vivo instability of CFZ are considered major drawbacks. We investigated whether a nanocrystal (NC) formulation can address these issues and enhance anticancer efficacy of CFZ against breast cancer. The surface of NC was coated with albumin in order to enhance the formulation stability and drug delivery to tumors via interactions with albumin-binding proteins located in and near cancer cells. The novel albumin-coated NC formulation of CFZ (CFZ-alb NC) displayed improved metabolic stability and enhanced cellular interactions, uptake and cytotoxic effects in breast cancer cells in vitro. Consistently, CFZ-alb NC showed greater anticancer efficacy in a murine 4T1 orthotopic breast cancer model than the currently used cyclodextrin-based formulation. Overall, our results demonstrate the potential of CFZ-alb NC as a viable formulation for breast cancer therapy.

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GPR40 has been considered a potential therapeutic target for type 2 diabetes because activation of GPR40 stimulates insulin secretion when glucose levels increased. Fasiglifam, a GPR40 agonist, was withdrawn from clinical development in Phase III due to DILI. Therefore, we evaluated the safety profiles of IDG-16177, a novel GPR40 agonist. The potential for IDG-16177 to have off-target effects was assessed in a panel of 173 binding assays. 10 μM IDG-16177 demonstrated activity (>50% inhibition) against DP, EP2, EP3 and EP4 with 81, 83, 57 and 67 % inhibition, respectively. In a functional assay against the same targets, IDG-16177 was inactive in agonist and antagonist mode except for DP with 62.2% activity inhibition at a concentration of 10 μM. IDG-16177 and fasiglifam showed the similar level of hepatotoxic response in HμRELToxTM assay. Formation of reactive metabolite and covalent binding to proteins was evaluated in human hepatocytes. IDG-16177 shows lower covalent binding burden at expected human efficacious dose (0.3~1 mg) than fasiglifam. Transporter inhibitory potential of IDG-16177 was assessed in hepatic transporter-expressing membrane vesicles. IDG-16177 and fasiglifam showed the similar inhibition level of BSEP, MRP2, MRP3, and MRP4. But clinically predicted plasma concentration of IDG-16177 is lower than that of fasiglifam, so the safety margin of IDG-16177 is wider than that of fasiglifam. A core battery of safety pharmacology was evaluated and IDG-16177 did not induce adverse effect in all studies. A 4-week toxicity study was conducted in rats and monkeys, and the liver was determined as the target organ in monkeys. The NOAEL was over 60-fold than in vivo efficacy dose. IDG-16177 was not genotoxic in Ames test, in vitro and in vivo micronucleus test. And no phototoxicity was observed in in vitro 3T3 NRU study. These results shows that the potential for IDG-16177, a safe and effective GPR40 agonist, to treat patients with type 2 diabetes. Disclosure J. Yoon: None. J. Kim: None. K. An: None. C. Hong: None. H. Kwak: None. I. Je: None. H. Song: None. H. Song: None. J. Kim: None. S. Lee: None. C. Shin: None. Y. Jun: None. D. Hong: None. D. Lee: None. E. Jang: None.

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GPR40/FFAR1 is a G-protein-coupled receptor predominantly expressed in pancreatic β-cells. GPR40 agonists are known to stimulate insulin secretion and reduce circulating glucose levels in a glucose-dependent manner. Currently, IDG-16177, as a GPR40 agonist, is being developed by ildong Pharma in first-in-human study. IDG-16177 is a high potency and orally available small molecule agonist. IDG-16177 confirmed linear pharmacokinetic properties and is more potent than fasiglifam from in vivo studies. The oral bioavailability of IDG-16177 was 84.3, 75.4, and 71% in mice, rats, and monkeys, showing high oral absolute bioavailability in preclinical species. The Cmax and AUC values of IDG-16177 increased in a dose-proportional manner in a dose range of 0.3 to 10 mg/kg in mice and rats and 0.3 to 3 mg/kg in monkeys. In vivo long-term glucose-lowering effect was determined by oral glucose tolerance test (OGTT) in Sprague-Dawley (SD) rats and Otsuka Long-Evans Tokushima Fatty (OLETF) rats, respectively. IDG-16177 showed dose-dependently improvement of glucose tolerance in a multiple dosing study using SD and OLETF rats. In both in vivo tests, IDG-16177 0.3 mg/kg showed similar effective in glucose tolerance fasiglifam 10 mg/kg, respectively. In addition, IDG-16177 had a positive effect on fasting blood glucose, insulin, and glucagon in the long-term administration of OLETF rats. In these study, Cmax,ss of IDG-16177 showed approximately 60 times lower than those of fasiglifam and AUCss of IDG-16177 showed approximately 170 times lower than those of fasiglifam. In another study, the Glucose-stimulated insulin secretion effect of IDG-16177 was assessed in Male SD rat. IDG-16177 1 mg/kg showed similar effective in insulin secretion fasiglifam 10 mg/kg. These results show that IDG-16177 might be an effective drug candidate for treatment of type 2 diabetes. Disclosure J. Yoon: None. Y. Jun: None. K. An: None. C. Hong: None. H. Kwak: None. I. Je: None. H. Song: None. D. Lee: None. J. Kim: None. D. Hong: None. C. Shin: None. E. Jang: None. J. Kim: None. H. Song: None. S. Lee: None.

G-protein-coupled receptor 40 (GPR40/FFA1/FFAR1), a clinically validated anti-diabetes target, enhances insulin secretion in type 2 diabetes. It is known that the effect of glucose-stimulated insulin secretion (GSIS) in pancreatic β cells is mediated primarily through Gq. However, in a recent study, it was found that GPR40 plays a role in both G protein-mediated and β-arrestin-mediated mechanisms, and fasiglifam (TAK-875), a partial GPR40 agonist discontinued in phase 3 clinical trials, induces insulin secretion by mediating β-arrestin rather than Gq. Therefore, by using stable GPR40 cell lines and β cells, we tried to confirm the signaling mechanism and efficacy of IDG-16177, which is being developed by Ildong Pharma in first-in-human study, as a GPR40 agonist. In cells expressing recombinant human, rat, and cynomolgus monkey GPR40, IDG-16177 dose-dependently increases intracellular free Ca2+ level, with EC50 of 114.3, 103.9, and 758.8 nM, respectively, showing no significant differences between human and rat (fasiglifam EC50= 75.2, 140.4, and 906.2 nM). IDG-16177 enhances β-arrestin recruitment, which has been shown to contribute to GPR40-mediated GSIS, with an EC50 of 68.0 nM and Emax of 99.4%, and is more efficacious and potent than fasiglifam (EC50= 154.0 nM; Emax= 88.0%). IDG-16177 exhibits EC50 of 0.8 nM and 110.6 nM, in inositol phosphate 1 (IP1) accumulation assay and extracellular signal-regulated kinase (ERK) activation assay, respectively. Although IDG-16177 shows no signal at the cAMP pathway like fasiglifam, IDG-16177 (0.1~3 μM)-treated group enhances more insulin secretion than fasiglifam (1~10 μM) in HIT-T15 β cells. These studies support the potential utility of IDG-16177 for the treatment of type 2 diabetes. Disclosure J. Yoon: None. Y. Jun: None. K. An: None. C. Hong: None. H. Kwak: None. I. Je: None. H. Song: None. H. Song: None. D. Lee: None. J. Kim: None. D. Hong: None. C. Shin: None. E. Jang: None. J. Kim: None. S. Lee: None.