A series of indolyl acrylamide derivatives was synthesized as potential diacylglycerol acyltransferase (DGAT) inhibitors. Furfurylamine containing indolyl acrylamide derivative 5h exhibited the most potent DGAT inhibitory activity using microsomes prepared from rat liver. Further evaluation against human DGAT-1 and DGAT-2 identified indolyl acrylamide analogues as selective inhibitors against human DGAT-2. In addition, the most potent compound 5h inhibited triglyceride synthesis dose-dependently in HepG2 cell lines.

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LW6 (3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid methyl ester) is a potent inhibitor of drug efflux by the breast cancer resistance protein (BCRP). However, its poor aqueous solubility leads to low bioavailability, which currently limits in vivo applications. Therefore, the present study aimed to develop ternary solid dispersion (SD) formulations in order to enhance the aqueous solubility and dissolution rate of LW6. Various SDs of LW6 were prepared using a solvent evaporation method with different drug/excipient ratios. The solubility and dissolution profiles of LW6 in different SDs were examined, and F8-SD which is composed of LW6, poloxamer 407, and povidone K30 at a weight ratio of 1:5:8 was selected as the optimal SD. The structural characteristics of F8-SD were also examined using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and scanning electron microscopy (SEM). In the acidic to neutral pH range, F8-SD achieved rapid dissolution with a drug release of 76–81% within 20 min, while the dissolution of pure LW6 was negligible. The XRPD patterns indicated that F8-SD probably enhanced the solubility and dissolution of LW6 by changing the drug crystallinity to an amorphous state, in addition to the solubilizing effect of the hydrophilic carriers. Furthermore, F8-SD significantly improved the oral bioavailability of topotecan, which is a BCRP substrate, in rats. The systemic exposure of topotecan was enhanced approximately 10-fold by the concurrent use of F8-SD. In conclusion, the ternary SD formulation of LW6 with povidone K30 and poloxamer 407 appeared to be effective at improving the dissolution and in vivo effects of LW6 as a BCRP inhibitor.

No abstract

LW6, an (aryloxyacetylamino)benzoic acid derivative, was recently identified to be an inhibitor of hypoxia-inducible factor-1α (HIF-1α), which is an attractive target for cancer therapeutics. Although LW6 is known to act by inhibiting the accumulation of HIF-1α, pharmacokinetics needs to be evaluated to assess its potential as an anti-tumor agent. Here, we investigated the plasma pharmacokinetics and metabolism of LW6 in mice. LW6 exhibited a small volume of distribution (0.5 ± 0.1 L/kg), and a short terminal half-life (0.6 ± 0.1 hr). Following intravenous or oral administration, LW6 was rapidly converted to its active metabolite, (4-adamantan-1-yl-phenoxy)acetic acid (APA). Although LW6 was rapidly absorbed, its oral bioavailability, estimated using AUClastvalues, was low (1.7 ± 1.8 %). It was slowly degraded in mouse liver microsomes (t1/2 > 1 hr) and serum (t1/2 > 6 hr). About 54% or 44.8% of LW6 was available systemically as APA in the mouse after a single intravenous or oral administration, respectively. Thus, our results indicated the need to simultaneously consider the active metabolite as well as the parent compound for successful evaluation during lead optimization.

AC1497 is an effective dual inhibitor of malate dehydrogenase 1 and 2 targeting cancer metabolism. However, its poor aqueous solubility results in low bioavailability, limiting its clinical development. This study was conducted to develop an effective self-nanoemulsifying drug delivery system (SNEDDS) of AC1497 to improve its oral absorption. Based on the solubility of AC1497 in various oils, surfactants, and cosurfactants, Capryol 90, Kolliphor RH40, and Transcutol HP were selected as the components of SNEDDS. After testing various weight ratios of Capryol 90 (20–30%), Kolliphor RH40 (35–70%), and Transcutol HP (10–35%), SNEDDS-F4 containing 20% Capryol 90, 45% Kolliphor RH40, and 35% Transcutol HP was identified as an optimal SNEDDS with a narrow size distribution (17.8 ± 0.36 nm) and high encapsulation efficiency (93.6 ± 2.28%). Drug release from SNEDDS-F4 was rapid, with approximately 80% of AC1497 release in 10 min while the dissolution of the drug powder was minimal (<2%). Furthermore, SNEDDS-F4 significantly improved the oral absorption of AC1497 in rats. The maximum plasma concentration and area under the plasma concentration–time curve of AC1497 were, respectively 6.82- and 3.14-fold higher for SNEDDS-F4 than for the drug powder. In conclusion, SNEDDS-F4 with Capryol 90, Kolliphor RH40, and Transcutol HP (20:45:35, w/w) effectively improves the solubility and oral absorption of AC1497.

) is a proinflammatory cytokine that plays a key role in the pathogenesis and physiology of inflammatory and autoimmune diseases, such as coronary heart disease, cancer, Alzheimer's disease, asthma, rheumatoid arthritis, and most recently COVID-19. IL-6 and its signaling pathway are promising targets in the treatment of inflammatory and autoimmune diseases. Although, anti-IL-6 monoclonal antibodies are currently being used in clinics, huge unmet medical needs remain because of the high cost, administration-related toxicity, lack of opportunity for oral dosing, and potential immunogenicity of monoclonal antibody therapy. Furthermore, nonresponse or loss of response to monoclonal antibody therapy has been reported, which increases the importance of optimizing drug therapy with small molecule drugs. This work aims to provide a perspective for the discovery of novel small molecule IL-6 inhibitors by the analysis of the structure−activity relationships and computational studies for protein−protein inhibitors targeting the IL-6/IL-6 receptor/gp130 complex.

Recent development of the chemical inhibitors specific to oncogenic KRAS (Kirsten Rat Sarcoma 2 Viral Oncogene Homolog) mutants revives much interest to control KRAS-driven cancers. Here, we report that AIMP2-DX2, a variant of the tumor suppressor AIMP2 (aminoacyl-tRNA synthetase-interacting multi-functional protein 2), acts as a cancer-specific regulator of KRAS stability, augmenting KRAS-driven tumorigenesis. AIMP2-DX2 specifically binds to the hypervariable region and G-domain of KRAS in the cytosol prior to farnesylation. Then, AIMP2-DX2 competitively blocks the access of Smurf2 (SMAD Ubiquitination Regulatory Factor 2) to KRAS, thus preventing ubiquitin-mediated degradation. Moreover, AIMP2-DX2 levels are positively correlated with KRAS levels in colon and lung cancer cell lines and tissues. We also identified a small molecule that specifically bound to the KRAS-binding region of AIMP2-DX2 and inhibited the interaction between these two factors. Treatment with this compound reduces the cellular levels of KRAS, leading to the suppression of KRAS-dependent cancer cell growth in vitro and in vivo. These results suggest the interface of AIMP2-DX2 and KRAS as a route to control KRAS-driven cancers.