PubMed | Seoul National University, Chong Kun Dang Research Institute, Samsung, National Institute of Health and 2 more.
Type: | Journal: Stem cells international | Year: 2017
The Charcot-Marie-Tooth disease 2F (CMT2F) and distal hereditary motor neuropathy 2B (dHMN2B) are caused by autosomal dominantly inherited mutations of the heat shock 27kDa protein 1 (
Choi M.J.,Korea Institute of Science and Technology |
Choi M.J.,Ewha Womans University |
No E.S.,Korea Institute of Science and Technology |
Thorat D.A.,Korea Institute of Science and Technology |
And 15 more authors.
Journal of Medicinal Chemistry | Year: 2013
A series of aryloxazole, thiazole, and isoxazole derivatives was synthesized as vascular-targeting anticancer agents. Antiproliferative activity and tumor vascular-disrupting activity of all of the synthesized compounds were tested in vitro using various human cancer cell lines and HUVECs (human umbilical vein endothelial cells). Several compounds with an arylpiperazinyl oxazole core showed excellent cytotoxicity and metabolic stability in vitro. Among this series, two representative compounds (6-48 and 6-51) were selected and tested for the evaluation of anticancer effects in vivo using tumor-bearing mice. Compound 6-48 effectively reduced tumor growth (42.3% reduction in size) at the dose of 100 mg/kg. We believe that compound 6-48 will serve as a good lead compound for antimitotic and vascular-disrupting agents; further investigation to improve the in vivo efficacy of this series is underway. © 2013 American Chemical Society.
Tolerability and Pharmacokinetics of Lobeglitazone (CKD-501), a Peroxisome Proliferator-Activated Receptor-γ Agonist: A Single- and Multiple-Dose, Double-Blind, Randomized Control Study in Healthy Male Korean Subjects
Kim J.W.,Seoul National University |
Kim J.-R.,Seoul National University |
Yi S.,Seoul National University |
Shin K.-H.,Seoul National University |
And 7 more authors.
Clinical Therapeutics | Year: 2011
Background: Lobeglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist with partial PPAR-α affinity, was developed to treat type 2 diabetes mellitus. Objective: This study's aim was to evaluate the tolerability and pharmacokinetic (PK) properties of lobeglitazone to satisfy regulatory requirements for marketing approval in Korea. Methods: A block-randomized, double-blind, placebo-controlled, single- and multiple-dose study was conducted in healthy subjects. In the pilot study, 4 subjects were administered 0.5 mg, including 1 receiving a placebo. Then, the single-dose study was conducted with 1, 2, 4, and 8 mg doses (8 subjects in each group, including 2 receiving placebos), followed by the multiple-dose study with 1, 2, and 4 mg doses (once daily for 7 days; 8 subjects in each group, including 2 receiving placebos). Serial samples of blood and urine were collected and drug concentrations were determined by high turbulence liquid chromatography-LC/MS/MS. Tolerability assessments were performed throughout the study. Adverse events (AEs) were determined from general health-related questions and self-reports. Results: Thirty-six (mean [SD]; age, 23.6 [2.7] years; weight, 70.0 [6.9] kg) and 25 Korean male subjects (age, 23.5 [3.1] years; weight 69.4 [9.4] kg) were enrolled in the single- and multiple-dose studies, respectively. The data from subjects administered lobeglitazone who completed the study (27, single; 18, multiple) was included in the PK analyses. In the single-dose study, the AUC and C max of lobeglitazone increased with the dose. After repeated dosing for 7 days, the accumulation ratio ranged from 1.1 to 1.4. A total of 25 AEs were reported by 11 (30.6%) and 8 subjects (33.3%) in the single- and multiple-dose studies, respectively. All AEs were mild in intensity and not serious. Conclusions: Lobeglitazone was well tolerated in this small, selected group of healthy male Korean volunteers. The AUC and C max of lobeglitazone increased in a dose-proportional manner from 1 to 4 mg. © 2011 Elsevier HS Journals, Inc.
Kim Y.I.,Seoul National University |
Kim K.W.,University of Ulsan |
Lee H.K.,Seoul National University |
Park J.,Seoul National University |
And 6 more authors.
Anticancer Research | Year: 2014
Aim: To evaluate the anticancer efficacy of CKD-516, a novel vascular-disrupting agent, alone and in combination with doxorubicin in the treatment of hepatocellular carcinoma (HCC). Materials and Methods: In mice bearing luciferized HCC cells, therapeutic efficacy was assessed for seven days after single administration of CKD-516, doxorubicin, or combination of CKD-516 and doxorubicin. Results: Bioluminescence-imaging (BLI) signals in the CKD-516 group abruptly decreased initially, but recovered at seven days after treatment. BLI signals in the doxorubicin group gradually decreased over the 7-day period. In the combination group, BLI signals were abruptly reduced and remained suppressed for the 7-day period. On histopathological examination, CKD-516-treated tumors showed extensive central necrosis, whereas the peripheral layers remained viable. Doxorubicin-treated tumors showed mild and scattered necrosis. Tumors from the combination group showed more extensive central and peripheral necrosis, with smaller viable peripheral layers than the CKD-516 group. Conclusion: Combination therapy can have additive effects for treatment of HCC compared with CKD-516 or doxorubicin monotherapy.
Lee J.,Chong Kun Dang Research Institute |
Kim S.J.,Chong Kun Dang Research Institute |
Choi H.,Chong Kun Dang Research Institute |
Kim Y.H.,Chong Kun Dang Research Institute |
And 10 more authors.
Journal of Medicinal Chemistry | Year: 2010
Tubulin polymerization inhibitors had emerged as one of promising anticancer therapeutics because of their dual mechanism of action, i.e. apoptosis by cell-cycle arrest and VDA, vascular disrupting agent. VDAs are believed to be more efficient, less toxic, and several of them are currently undergoing clinical trials. To identify novel tubulin inhibitors that possess potent cytotoxicity and strong inhibition of tubulin polymerization as well as potent in vivo antitumor efficacy, we have utilized benzophenone scaffold. Complete SAR analysis of newly synthesized analogues that were prepared by incorporation of small heterocycles (C2, C4, and C5 position) into B-ring along with the evaluation of their in vitro cytotoxicity, tubulin polymerization inhibition, and in vivo antitumor activity allowed us to identify 22 (S516). Compound 22 was found to have potent cytotoxicity against several cancer cells including P-gp overexpressing MDR positive cell line (HCT15). It also induced cell cycle arrest at G2/M phase, which is associated with strong inhibition of tubulin polymerization. Its in vivo efficacy was improved by preparing its (l)-valine prodrug, 65 (CKD-516), which together with greatly improved aqueous solubility has shown marked antitumor efficacy against both murine tumors (CT26 and 3LL) and human xenogratfs (HCT116 and HCT15) in mice. © 2010 American Chemical Society.
PubMed | Chong Kun Dang Research Institute and Seoul National University
Type: | Journal: Oncotarget | Year: 2016
There have been extensive efforts to improve the outcome of glioblastoma, but the prognosis of this disease has not been significantly altered to date. Histone deacetylase inhibitors (HDACIs) have been evaluated as promising anti-cancer drugs and regulate cell growth, cell cycle arrest and apoptosis in glioblastoma. Here, we demonstrated the therapeutic efficacy of a novel pan-HDACI, 7-ureido-N-hydroxyheptanamide derivative (CKD5), compared with traditional pan-HDACIs, such as suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA), in vitro and in vivo. Compared with SAHA and TSA, CKD5 had improved cytotoxic effects and induced apoptosis, anti-proliferative activity and cell cycle arrest at G2/M phase. Furthermore, CKD5 significantly reduced tumor volume and prolonged the survival in vivo compared with TSA, suggesting improved anti-cancer efficacy among HDACIs. Our results demonstrate that the novel HDACI CKD5 is a promising therapeutic candidate for glioblastoma.
PubMed | Chong Kun Dang Research Institute, Kangwon National University and Seoul National University
Type: | Journal: Biopharmaceutics & drug disposition | Year: 2015
The pharmacokinetics of lobeglitazone (LB) was studied after intravenous administration at a dose of 1 mg/kg and oral administration at doses of 0.1, 1 and 10 mg/kg in male and female rats. The area under the plasma concentration-time curve from time zero to infinity (AUC
PubMed | Chong Kun Dang Research Institute and Korea Institute of Science and Technology
Type: Journal Article | Journal: Chemical biology & drug design | Year: 2015
Microtubules are important cellular component that are critical for proper cellular function. Microtubules are synthesized by polymerization of tubulin heterodimers called protofilaments. Microtubule dynamics facilitate proper cell division during mitosis. Disruption of microtubule dynamics by small-molecule agents inhibits mitosis, resulting in apoptotic cell death and preventing cell cycle progression. To identify a novel small molecule that binds the tubulin interface to affect microtubule dynamics, we developed a bioactive conformation alignment pharmacophore (BCAP) model to screen tubulin inhibitors from a huge database. The application of BCAP model generated based on the known -tubulin interface binders enabled us to identify several small-molecules that cause apoptosis in human promyelocytic leukemia (HL-60) cells. Virtual screening combined with an invitro assay yielded 15 cytotoxic molecules. In particular, ethyl 2-(4-(5-methyl-3-nitro-1H-pyrazol-1-yl)butanamido)-4-phenylthiophene-3-carboxylate (H05) inhibited tubulin polymerization with an IC50 of 17.6m concentration. The virtual screening results suggest that the application of an unbiased BCAP pharmacophore greatly eliminates unlikely compounds from a huge database and maximizes screening success. From the limited compounds tested in the tubulin polymerization inhibitor (TPI) assay, compound H05 was discovered as a tubulin inhibitor. This compound requires further structure activity optimization to identify additional potent inhibitors from the same class of molecules.