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.
NUAK
isoforms, NUAK1 (ARK5) and NUAK2 (SNARK), are important members
of the AMPK family of protein kinases. They are involved in a broad
spectrum of physiological and cellular events, and sometimes their
biological roles overlap. NUAK isoform dysregulation is associated
with numerous pathological disorders, including neurodegeneration,
metastatic cancer, and diabetes. Therefore, they are promising therapeutic
targets in metabolic diseases and cancers; consequently, various NUAK-targeted
inhibitors have been disclosed. The first part of this review comprises
a brief discussion of the homology, expression, structure, and characteristics
of NUAK isoforms. The second part focuses on NUAK isoforms’
involvement in crucial biological operations, including mechanistic
findings, highlighting how their abnormal functioning contributes
to disease progression and quality of life. The third part summarizes
the key findings and applications of targeting NUAK isoforms for treating
multiple cancers and neurodegenerative disorders. The final part systematically
presents a critical review and analysis of the literature on NUAK
isoform inhibitions through small molecules.
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.
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