Jang-Sik Choi

G-749, a novel FLT3 kinase inhibitor, can overcome drug resistance for the treatment of acute myeloid leukemia

Aberrant activations of Fms-like tyrosine receptor kinase (FLT) 3 are implicated in the pathogenesis of 20% to 30% of patients with acute myeloid leukemia (AML). G-749 is a novel FLT3 inhibitor that showed potent and sustained inhibition of the FLT3 wild type and mutants including FLT3-ITD, FLT3-D835Y, FLT3-ITD/N676D, and FLT3-ITD/F691L in cellular assays. G-749 retained its inhibitory potency in various drug-resistance milieus such as patient plasma, FLT3 ligand surge, and stromal protection. Furthermore, it displayed potent antileukemic activity in bone marrow blasts from AML patients regardless of FLT3 mutation status, including those with little or only minor responses to AC220 or PKC412. Oral administration of G-749 yielded complete tumor regression and increased life span in animal models. Thus, G-749 appears to be a promising next-generation drug candidate for the treatment of relapsed and refractory AML patients with various FLT3-ITD/FLT3-TKD mutants and further shows the ability to overcome drug resistance.

Synthesis, characterization and properties of new fully n-alkylated 14-membered tetraaza macrocycles and their copper(II) complexes

Abstract New fully N-alkylated 14-membered tetraaza macrocyles 3,14-dimethyl- 3,14-dimethyl-2,6,13,17-tetraethyl-2,6,13,17-tetraazatricyclo[16.4.0.1.180.7.12]docosane (3) and 3,14-dimethyl-2,6,13,17-tetrakis(n-propyl)-2,6,13,17-tetraazatricyclo[16.4.01.180.7.12]docosane (4) have been prepared from direct reactions of 3,14-dimethyl-2,6,13,17-tetraazatricyclo [16.4.01.180.7.12]docosane (1) with appropriate alkyl bromides. The protonation constants of 3 and 4 were determined by a potentiometric method, and it was found that these ligands have a higher proton affinity than 1 and its tetra-N-methyl derivative (2). The new macrocyles react with the dehydrated copper(II) ion to form the stable complexes [Cu(L)]2+ ( L = 3 or 4 ) in an ethanol solution, but do not react with hydrated copper(II) or nickel(II) ions in the same solution. The effects of the N-alkyl groups on the protonation and complexation behaviours of the macrocycles and on the spectroscopic and redox properties of their copper(II) complexes are presented.

Quasi-SMILES-Based Nano-Quantitative Structure–Activity Relationship Model to Predict the Cytotoxicity of Multiwalled Carbon Nanotubes to Human Lung Cells

Quantitative structure-activity relationship (QSAR) models for nanomaterials (nano-QSAR) were developed to predict the cytotoxicity of 20 different types of multiwalled carbon nanotubes (MWCNTs) to human lung cells by using quasi-SMILES. The optimal descriptors, recorded as quasi-SMILES, were encoded to represent the physicochemical properties and experimental conditions for the MWCNTs from 276 data records collected from previously published studies. The quasi-SMILES used to build the optimal descriptors were (i) diameter, (ii) length, (iii) surface area, (iv) in vitro toxicity assay, (v) cell line, (vi) exposure time, and (vii) dose. The model calculations were performed by using the Monte Carlo method and computed with CORAL software ( www.insilico.eu/coral ). The quasi-SMILES-based nano-QSAR model provided satisfactory statistical results ( R2 for internal validation data sets: 0.60-0.80; R2pred for external validation data sets: 0.81-0.88). The model showed potential for use in the estimation of human lung cell viability after exposure to MWCNTs with the following properties: diameter, 12-74 nm; length, 0.19-20.25 μm; surface area, 11.3-380.0 m2/g; and dose, 0-200 ppm.

Highly potent and selective pyrazolylpyrimidines as Syk kinase inhibitors.

A series of pyrazolylpyrimidine scaffold based Syk inhibitors were synthesized and evaluated for their biological activities and selectivity. Lead optimization efforts provided compounds with potent Syk inhibition in both enzymatic and TNF-α release assay.

Crystal structures of spleen tyrosine kinase in complex with novel inhibitors: structural insights for design of anticancer drugs

Spleen tyrosine kinase (SYK) is a cytosolic nonreceptor protein tyrosine kinase that mediates key signal transduction pathways following the activation of immune cell receptors. SYK regulates cellular events induced by the B‐cell receptor and Fc receptors with high intrinsic activity. Furthermore, SYK has been regarded as an attractive target for the treatment of autoimmune diseases and cancers. Here, we report the crystal structures of SYK in complex with seven newly developed inhibitors (G206, G207, O178, O194, O259, O272, and O282) to provide structural insights into which substituents of the inhibitors and binding regions of SYK are essential for lead compound optimization. Our kinase inhibitors exhibited high inhibitory activities against SYK, with half‐maximal inhibitory concentrations (IC50) of approximately 0.7–33 nm, but they showed dissimilar inhibitory activities against KDR, RET, JAK2, JAK3, and FLT3. Among the seven SYK inhibitors, O272 and O282 exhibited highly specific inhibitions against SYK, whereas O194 exhibited strong inhibition of both SYK and FLT3. Three inhibitors (G206, G207, and O178) more efficiently inhibited FLT3 while still substantially inhibiting SYK activity. The binding mode analysis suggested that a highly selective SYK inhibitor can be developed by optimizing the functional groups that facilitate direct interactions with Asn499.

Crystal structure of pim1 kinase in complex with a pyrido[4,3-d]pyrimidine derivative suggests a unique binding mode.

Human Pim1 kinase is a serine/threonine protein kinase that plays important biological roles in cell survival, apoptosis, proliferation, and differentiation. Moreover, Pim1 is up-regulated in various hematopoietic malignancies and solid tumors. Thus, Pim1 is an attractive target for cancer therapeutics, and there has been growing interest in developing small molecule inhibitors for Pim1. Here, we describe the crystal structure of Pim1 in complex with a newly developed pyrido[4,3-d]pyrimidine-derivative inhibitor (SKI-O-068). Our inhibitor exhibits a half maximum inhibitory concentration (IC50) of 123 (±14) nM and has an unusual binding mode in complex with Pim1 kinase. The interactions between SKI-O-068 and the Pim1 active site pocket residue are different from those of other scaffold inhibitor-bound structures. The binding mode analysis suggests that the SKI-O-068 inhibitor can be improved by introducing functional groups that facilitate direct interaction with Lys67, which aid in the design of an optimized inhibitor.

Towards a generalized toxicity prediction model for oxide nanomaterials using integrated data from different sources

A generalized toxicity classification model for 7 different oxide nanomaterials is presented in this study. A data set extracted from multiple literature sources and screened by physicochemical property based quality scores were used for model development. Moreover, a few more preprocessing techniques, such as synthetic minority over-sampling technique, were applied to address the imbalanced class problem in the data set. Then, classification models using four different algorithms, such as generalized linear model, support vector machine, random forest, and neural network, were developed and their performances were compared to find the best performing preprocessing methods as well as algorithms. The neural network model built using the balanced data set was identified as the model with best predictive performance, while applicability domain was defined using k-nearest neighbours algorithm. The analysis of relative attribute importance for the built neural network model identified dose, formation enthalpy, exposure time, and hydrodynamic size as the four most important attributes. As the presented model can predict the toxicity of the nanomaterials in consideration of various experimental conditions, it has the advantage of having a broader and more general applicability domain than the existing quantitative structure-activity relationship model.

A Step-wise Elimination Method Based on Euclidean Distance for Performance Optimization Regarding to Chemical Sensor Array

Abstract In order to prevent drink-driving by detecting concentration of alcohol from driver’s exhale breath, twenty chemical sensors fabricated.The one of purposes for sensor array which consists of those sensors is to discriminate between target gas(alcohol) and interferencegases(CH 3 CH 2 OH, CO, NOx, Toluene, and Xylene). Wilks’s lambda was presented to achieve above purpose and optimal sensors wereselected using the method. In this paper, step-wise sensor elimination based on Euclidean distance was investigated for selecting optimalsensors and compared with a result of Wilks’s lambda method. The selectivity and sensitivity of sensor array were used for comparingperformance of sensor array as a result of two methods. The data acquired from selected sensor were analyzed by pattern analysis meth-ods, principal component analysis and Sammon’s mapping to analyze cluster tendency in the low space (2D). The sensor array by step-wise sensor elimination method had a better sensitivity and selectivity compared to a result of Wilks’s lambda method.Keywords: Step-wise sensor elimination, Array optimization, Wilks’s lambda

Short term Sensor's Drift Compensation by using Three Drift Correction Techniques

The ideal chemical sensor must show the similar result under the same condition for accurate measurement of gases regardless of time. However, the actual responses of chemical sensors have been shown the lacks of repeatability and reproducibility because of the drift which has been caused by aging and pollution of the sensor and the environment change such as temperature and humidity. If the problems are not properly taken into considerations, the stability and reliability of the system using chemical sensors would be decreased. In this paper, we analyzed the sensors drift and applied the three different compensation methods(DWT( Discrete Wavelets Transform), Baseline Manipulation, Internal Normalization) for reducing the effects of the drift in order to improve the stability and the reliability of short term of the chemical sensors. And in order to compare the results of the methods, the standard deviation was used as a criterion. The sensor drift was analyzed by a trend line graph. We applied the three methods to the successive data measured for three days and compared the results. As a result of comparison, the standard deviation of DWT showed lowest value. (Before compensation: 7.1219, DWT: 1.3644, Baseline Manipulation: 2.5209, Internal Normalization: 3.1425)

Implementation of Demo Program for Visual Communication in Compliance with MPEG-21 Part 22: User Description

ISO/IEC JTC1/SC29WG11 MPEG has been standardizing UD(user description) to give a user personalized recommendation services. Besides, CD(context description), service description(SD), and recommendation description(RD) are recently being standardized by UD Adhoc Group in MPEG with an advanced UD to cope with needs of current and upcoming services such as augmented reality and social network. The descriptions was reflected to MPEG-UD WD(Working Draft) at MPEG 107th meeting and the document was finally approved as international standard by national bodies with standard number(ISO/IEC IS 21000-22 UD) at 114th MPEG meeting. In addition, reference software WD to validate conformance of UD standard was approved at 113th MPEG meeting. In this paper, we developed a demo program for visual communication according to guideline defined in reference software WD to validate the reference software as well as UD standard.