research
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1. Development of B-Raf kinase inhibitors as anticancer agent : Structure-based Drug Design
The Ras/Raf/Mek/Erk Pathway, a cell signaling network for cell survival, growth, and proliferation, is a well-known target for cancer treatment. In this pathway, Raf kinase has been the most studied drug target since mutations of the Raf protein were found in approximately 7% of human cancers with particularly high frequency in melanoma (50~70 %), ovarian (35 %), thyroid(30%),and colorectal(10 %) cancers. In many case studies on the Raf mutations, the motst frequent mutation of Raf protein(>85%)is valine substitution by glutamic acid at position 600(v600E), which shows a 500-fold increase in catalytic activity, providing cancer cells with both proliferation and survival signals. Therefore,bRafV600E is a high-interest therapeutic target for the treatment of human cancers. In addition, there is now growing consensus being made that cRaf is also associated significantly with disease progression and cell proliferation in a subset of melanoma. Here, developing selective B-Raf V600E inhibitor as anticancer agents is much of interest. We are investigating to develop novel B-Raf V600E inhibitors structure-basis. The various scaffold of novel B-RafV600E inhibitors are designed and being synthesized via molecular modeling and rapid organic synthesis.
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2. Development of JNK inhibitors as therapeutics for neurodegenerative diseases. : Fragment-based drug discovery (in-silico, and NMR-, X-ray based)
The c-Jun N-terminal kinases (JNKs)/stress activated protein kinases (SAPKs) are mitogen-activated protein kinases (MAPKs) that can be activated in response to various stimuli such as cytokines, mitiogens, osmotic stress and ultraviolet irradiation. Activated JNK leads to the phosphorylation of a number of transcription factors related to apoptosis.1 of the three isoforms (JNK1, 2, and 3), JNK3 is predominantly localized to the brain and testes and has a potential unique role in central nervous system (CNS) disorders. 2 Therefore JNK3 has attracted attention as a suitable therapeutic target for neurodegenerative diseases such as Alzheimer’s and Parkinsonian diseases in addition to ischemic injury. Here we are interested in developing selective JNK inhibitors based on fragment-based drug discovery. Currently, we established kinased-focused fragment library, and screening results are being used in designing novel inhibitors of JNK3.