Copyright © 2018 Chemical Kinomics lab.

Chemical Biology

Target Identification

   Chemical biology is the study of the chemicals and chemical reactions involved in biological processes, incorporating the disciplines of bio-organic chemistry, biochemistry, cell biology, and pharmacology. It mainly solves biological problems through searching unknown targets for pharmacological small molecules or finding ligands for well-defined drug targets. The identification of the targets of biologically active molecules is an important step in the field of chemical biology.

   Target identification is the process of identifying the molecular target of a small molecule and understanding off-target effects for a drug that demonstrates a toxicological phenotype. It can be approached by direct biochemical methods, computational inference, or genetic interactions. Combinations of these approaches may be required to fully understand mechanisms of small-molecule action.

   Our recent accomplishments include:

   Kinase in Cancer : Identification of ACK, GCK novel targets with NRAS mutation in acute leukemias
 

  • We have identified GNF-7 as a multi-targeted kinase inhibitor of cells transformed by NRAS  through chemical screening using the Ba/F3-NRAS-G12D cell line.

  • By utilizing GNF-7 as a tool compound, we used the method of KiNativ profiling, cell-based screening; knock down to find the novel target of GNF-7. 

  • Mechanistic analysis revealed that ACK1/AKT and GCK were functionally important novel therapeutic targets of acute leukemia with NRAS mutation. 

  • We demonstrated that it is possible to devise efficient cell-based screening paradigms to identify targets that are important only in the context of mutant NRAS signaling, and are thus synthetically lethal.

   Kinase in Neuronal disease

  • The human brain does not produce new neuron in the adult central nervous system. A common recovery after injury is the reorganization of functions using remaining intact system. In general, regeneration of the central nervous system is blocked by three barriers. Brain tissue wounds lead to neuronal deathand other types of cells, such as glial cells, inhibit axonal growth, limiting the ability to divide, differentiate, and migrate as most adult neural stem cells do. After injury, the remaining neuronal circuits are reorganized by changing the activated pattern to restore their function but the way it works has not been revealed yet.

  • We first focused on the phenotype-based screening. We have used high-throughput screening to confirm that some compounds can regulate neuronal systems.  Next, we aimed  to find a new target and to elucidate the mechanism  regulating neuro-degeneration by using tool compounds.

   Kinase in Immuno-oncology

  • Immunotherapy is one of the latest and most spotlighted strategies to treat cancer. Especially, the methods using immune check-point blockade and chimeric antigen receptor T-cell are showing successful clinical outcomes. However, present immune therapies have several restrictions like its narrow coverage on cancer types and limited patient population with good efficacy. Our goal is to identify small molecules that can enhance the effect of immune therapies. We put emphasison inhibiting immune checkpoint molecules and modulating the cancer microenvironment for extended cancer targets.

  • PD-1 and PD-L1 interaction,  a powerful means for cancer to evade immune system, is mainly targeted by monoclonal antibodies. We are making an effort to find out a small molecule that can increase the efficacy of those antibody treatments.

  • We are also interested in regulating MDSC (Myeloid-derived suppressor cell) which is a group of heterogenous immune cells that tends to regulate other immune cells negatively. Comprehending the underlying mechanism of its suppressive function and discovering small molecules that can control MDSC is our goal of study.

Drug Repositioning

   Our research interest is not  only to develop novel small molecules, but also to reposition existing drugs. Drug repositioning is a method of drug development that finds new medical uses of drugs that are already on the market or failed to industrialize for reasons other than stability at the clinical stage. In contrast to de-novo drug discovery process which  takes a long time and huge cost, drug repositioning strategies can reduce the time and money by minimizing safety assessments and lead optimization steps. Especially, in the field of anticancer drug, expanding indications to new cancer type has been in the limelight as a way to overcome the inefficiency of drug discovery process and to increase the value of existing drugs.

   Our recent accomplishments include:

   Expanding indications for AZD4547

  • We demonstrated an antitumor effect of AZD4547 against endometrial cancers for the first time. 

  • Through phospho-kinase array, reporter gene assay, and genome-wide transcriptome analysis, we identified the significance of the FGFR2–EGR1 axis in progression of endometrial cancers. In addition, Kinome-wide inhibition profiling results suggest potential new targets of AZD4547, including MAP4K3, MAP4K5, IRR, RET, and FLT3.