Chemical biology is a field of study that spans the disciplines of chemistry and biology through exploring biological phenomena by appropriate use of small molecules. Chemical biology involves application of chemical tools, for instance, kinase inhibitors in order to manipulate function of proteins, which makes it distinctive from conventional biology that generally makes use of genetic tools (siRNA, Random mutagenesis) instead. Our main interest in chemical biology is to identify and modulate certain interaction between small molecules and proteins that can further be developed as a potential therapeutic foundation for various diseases.
Our recent accomplishments include:
Allosteric inhibitors of Bcr-abl–dependent cell proliferation
(Nat Chem Biol. 2006 , 2(2):95-102.)
Using an affinity chromatography with immobilized compounds(GNF-3/4), we found that GNF-2 is an allosteric non-ATP competitive inhibitor which is a new class of compound that inhibits Bcr-abl kinase activity.
Unlike binding mode of imatinib to ATP biding pocket of Bcr-abl, GNF-2 binds to myristoyl pocket distant from the active site. This unique binding mode of GNF-2 provides exceptional kinase selectivity as well as excellent cellular potency.
Our result would provide a starting point for development of new class drugs such as leukemia-specific agents with no off-target effect.
Identification of novel therapeutic targets in acute leukemias with NRAS mutations using a pharmacologic approach
(Blood. 2015, 14;125(20):3133-43.)
GNF-7, a multi-target kinase inhibitor, shows selective growth inhibition toward NRAS mutant Acute Myeloid Leukemia cells.
Based on the KiNativ assay and in-vitro biochemical kinase assay, we identified dual inhibition of ACK1 and GCK (synthetically lethal of ACK1 and GCK) as a novel therapeutic approach for acute leukemia with NRAS mutation.
Contrasted with RNA interference, a multi-target kinase inhibitor, which is able to inhibit multiple kinases simultaneously, can provide clues of a synthetic lethal target.
Identification of MAPK X as a novel therapeutic target for melanoma by using selective MAPK X inhibitor
Among our in-house kinase inhibitors, SIJ149966 compound selectively inhibits the kinase activity of MAPK X, which belongs to Mitogen-activated protein kinases family. We found out that SIJ149966 compound, a novel and specific MAPK X inhibitor, shows anti-proliferative activity against melanoma cancer cells implying that MAPK X would be a potential therapeutic target for melanoma treatment.
MAPKs (Mitogen-activated protein kinases), a family of cascade signal transduction proteins consisted of MAP Kinase (MAP1K), MAP2K, MAP3K and MAP4K is involved in tumorigenesis, as well as in diverse cellular function. ERK, p38, and JNK are representative MAP kinases in the downstream of MAPKs cascade signal transduction.
Biological functions of several MAPKs are well studied. However, the function of MAPK X, a target kinase of SIJ149966 has not been fully understood. Our current pursuit in this research is to elucidate biological function of novel MAPK X in terms of tumorigenesis in diverse cancer cells as well as melanoma.
"Illustration reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com)"