So Ha Lee

ROS receptor tyrosine kinase: a new potential target for anticancer drugs

ROS kinase is one of the last two remaining orphan receptor tyrosine kinases with an as yet unidentified ligand. The normal functions of human ROS kinase in different body tissues have not been fully identified so far. However, the ectopic expression, as well as the production of variable mutant forms of ROS kinase has been reported in a number of cancers, such as glioblastoma multiforme, and non‐small cell lung cancer, suggesting a role for ROS kinase in deriving such tumors. It is thought also that c‐ROS gene may have a role in some cardiovascular diseases, and the fact that homozygous male mice targeted against c‐ROS gene are healthy but infertile, has inspired researchers to think about ROS inhibition as a method for development of new male contraceptives. The recent discovery of new selective and potent inhibitors for ROS kinase, along with the development of new specific diagnostic methods for the detection of ROS fusion proteins, raises the importance of using these selective inhibitors for targeting ROS mutations as a new method for treatment of cancers harboring such genes. This review focuses on the ectopic expression of ROS and its fusion proteins in different cancer types and highlights the importance of targeting these proteins for treatment of substantial cancers. It describes also the recent advances in the field of ROS kinase inhibition, and the potential clinical applications of ROS kinase inhibitors.  © 2010 Wiley Periodicals, Inc. Med Res Rev 31: 794‐818, 2011

Synthesis of pyrrolo[2,3-d]pyrimidine derivatives and their antiproliferative activity against melanoma cell line

Synthesis of a new series of diarylureas and amides having pyrrolo[2,3-d]pyrimidine scaffold is described. Their in vitro antiproliferative activities against A375 human melanoma cell line and HS 27 fibroblast cell line were tested and the effect of substituents on pyrrolo[2,3-d]pyrimidine was investigated. The newly synthesized compounds, except N-acetyl derivatives (Id, Ie, and Im), generally showed superior or similar activity against A375 to Sorafenib. Among all of these derivatives, compounds Iq and Ir having imidazole and morpholine moieties, respectively, showed the most potent antiproliferative activity against A375.

New method for the preparation of (R)-carnitine

Abstract A new method for the preparation of ( R )-carnitine ( 1 ) has been developed from enantiomerically pure (R)-4- (trichloromethyl)-oxetan-2-one [(R)- 2 ] which was easily obtained from the [2+2]-cycloaddition of ketene and chloral in the presence of catalytic amounts of poly(acryloyl quinidine). The key intermediate, ethyl ( R )-3-hydroxy-4-chlorobutyrate [(R)- 5 ] , was prepared by ethanolysis of (R)- 2 followed by selective bis-dechlorination of ethyl (R)-3- hydroxy-4,4,4-trichlorobutyrate [(R)- 3 ] .

Design, synthesis and biological evaluation of new potent and highly selective ROS1-tyrosine kinase inhibitor.

ROS1 protein is a receptor tyrosine kinase that has been reported mainly in meningiomas and astrocytomas, and until now, there is no selective inhibitor for this kinase. In this study, we illustrate for the synthesis of a highly potent and selective inhibitor for ROS1 kinase. The synthesized compound 1 was tested initially at a single dose concentration of 10 microM over 45 different kinases. At this concentration, a 94% inhibition of the enzymatic activity of ROS1 kinase was observed, while the inhibition in activity was below 30% in all of the other kinases. The pyrazole compound 1 was further tested in a 10-dose IC(50) mode and showed an IC(50) value of 199 nM for ROS1 kinase. The compound 1 can be used as a promising lead for the development of new selective inhibitors for ROS1 kinase, and it may open the way for new selective therapeutics for astrocytomas.

Design, synthesis, screening, and molecular modeling study of a new series of ROS1 receptor tyrosine kinase inhibitors

A series of rationally designed ROS1 tyrosine kinase inhibitors was synthesized and screened. Compound 12b has showed good potency with IC50 value of 209 nM, which is comparable with that of the reference lead compound 1. Molecular modeling studies have been performed, that is, a homology model for ROS1 was built, and the screened inhibitors were docked into its major identified binding site. The docked poses along with the activity data have revealed a group of the essential features for activity. Overall, simplification of the lead compound 1 into compound 12b has maintained the activity, while facilitated the synthetic advantages. A molecular interaction model for ROS1 kinase and inhibitors has been proposed.

Aminoquinoline derivatives with antiproliferative activity against melanoma cell line

The synthesis of a novel series of aminoquinoline derivatives 1a-p and their antiproliferative activities against A375 human melanoma cell line were described. Most compounds showed superior antiproliferative activities to Sorafenib as a reference compound. Among them, quinolinyloxymethylphenyl compounds 1k and 1l exhibited potent activities (IC(50)=0.77 and 0.79microM, respectively) and excellent selectivity against melanoma and fibroblast cell lines.

New diarylureas and diarylamides possessing acet(benz)amidophenyl scaffold: design, synthesis, and antiproliferative activity against melanoma cell line.

A series of new diarylurea and diarylamide derivatives possessing acet(benz)amidophenyl scaffold was synthesized. Their in vitro antiproliferative activity was tested against A375P human melanoma cell line. Compounds 1c,d and 2c,d showed the highest potencies with IC(50) values in sub-micromolar scale. In addition, compounds 1b,e,l and 2e,l were more potent than Sorafenib but with IC(50) values in micromolar range. Moreover, compound 2c was equipotent to Vemurafenib, and 2d showed higher potency than Vemurafenib against A375P. Molar refractometry calculation and ADME profiling of the highest potent four derivatives 1c,d and 2c,d are also reported.

Design and Synthesis of New Potent Anticancer Pyrazoles with High FLT3 Kinase Inhibitory Selectivity

A new series of 1H- and 2H-pyrazole derivatives (35 final compounds) has been designed and synthesized in this study. A selected group (13 compounds) was then tested over a panel of 60 cancer cell lines at a single dose concentration of 10microM. At this concentration, six compounds have showed moderate to strong mean inhibitions, and were further tested at five-dose testing mode to determine their IC(50) over the 60 cell lines. The IC(50) values of the tested compounds indicated high potency (as for compound 10f) as well as high efficacy (as for compound 11e). Accordingly, compound 10f was then tested at a single dose concentration of 10microM over a panel of 54 kinases to determine its kinase inhibitory profile. The compound has showed good selectivity towards FLT3 kinase, associated with a moderate potency, with an IC(50) value of 1.74microM.

Chemoenzymatic Synthesis of Optically Active 2-Phenyl-2-(1H-1,2,4-triazol-1-ylmethyl)hexanenitrile

Abstract (±)-2-Cyano-2-phenyl-1-hexanol 3 was resolved to each enantiomer using Candida rugosa and Pseudomonas fluorescens lipases in 62 and 99% ee, respectively. The absolute stereochemistry of one of the enantiomers was determined to be (S) by diastereomeric amide formation and X-ray crystallography. The resolved alcohols of (R)- and (S)-isomer were transformed to Systhane® analogues.

Structure-based optimization and biological evaluation of trisubstituted pyrazole as a core structure of potent ROS1 kinase inhibitors

Recently inhibition of ROS1 kinase has proven to be a promising strategy for several indications such as glioblastoma, non-small cell lung cancer (NSCLC), and cholangiocarcinoma. Our team reported trisubstituted pyrazole-based ROS1 inhibitors by which two inhibitors showed good IC₅₀ values in enzyme-based screening. To develop more advanced ROS1 inhibitors through SAR this trisubstituted pyrazole-based scaffold has been built. Consequently, 16 compounds have been designed, synthesized and shown potent IC₅₀ values in the enzymatic assay, which are from 13.6 to 283 nM. Molecular modeling studies explain how these ROS1 kinase inhibitors revealed effectively the key interactions with ROS1 ATP binding site. Among these compounds, compound 9a (IC₅₀=13.6 nM) has exerted 5 fold potency than crizotinib and exhibited high degree of selectivity (selectivity score value=0.028) representing the number of non-mutant kinases with biological activity over 90% at 10 μM.