Protein kinases are enzymes catalyzing transfer of the γ-phosphate of ATP to amino acid side chains in proteins, such as serine, threonine, and tyrosine. Imatinib, an Abelson tyrosine kinase inhibitor, is known to be the first kinase inhibitor approved in 2001 for the treatment of chronic myeloid leukemia. Since then, over 70 kinase inhibitors have been approved to cure cancers and infectious diseases, indicating that kinase inhibitors are well-validated drug targets. Although there are numerous issues to overcome, such as kinase selectivity and resistance, kinase inhibitors are at the center stage in the field of drug discovery. In our continuous and dedicated efforts to discover novel kinase inhibitors, our lab has focused on several kinase targets, such ALK, BTK, and JAK, ultimately to help patients suffering from cancers and autoimmune diseases. Based on our know-how to design and synthesize unique kinase inhibitors, currently several ongoing programs on kinase inhibitors have been pursued, leading to proprietary IP rights. Successfully developed inhibitors may have application feasibilities for protein degraders.

Targeted protein degradation is a rapidly emerging therapeutic intervention that induces protein degradation. Proteolysistargeting chimera (PROTAC) is a hetero-bifunctional molecule composed of a binder for target protein binding, a binder for E3 ubiquitin ligase binding, and a linker for connecting two binders. PROTAC promotes the formation of a ternary complex with the targeted protein and E3 ligase, leading to ubiquitination of the targeted protein and subsequent proteasomal degradation process. Currently, several E3 ubiquitin ligases, including b-TRCP, MDM2, cIAP, VHL, and cereblon (CRBN), have been used in PROTAC. By contrast, monomeric molecular glues (MG) are particularly attractive for drug discovery due to their relatively small size. The representative MGs are immunomodulatory drug (IMiDs) such as thalidomide, lenalidomide, and pomalidomide. IMidDs induce recruitment of neosubstrates such as transcription factors IKZF1 (Ikaros), and IKZF3 (Aiolos) to CRBN E3 ligase. CRBN-dependent poly-ubiquitination and subsequent degradation of these neosubstrates resulted in downregulation of IRF4 and MYC, as well as upregulation of IL-2 production in T cells. Based on this background, we are currently working on anticancer drug with target protein degradation mechanism .

​​ Originally proposed by Brenner and Lerner, DEL has emerged as a powerful high-throughput screening technology. In a DEL, each compound is conjugated with a DNA tag encoding its chemical structure. All library compounds are screened against the target in one pot based on binding affinity. Selected binders are decoded by PCR amplification and next-generation sequencing (NGS) to read the barcodes. DELs can contain hundreds of millions to many billions of compounds and screening can be rapidly performed in a few hours. In the past decade, DELs have been widely adopted by the pharmaceutical industry in many drug discovery programs and demands for DEL technology in drug discovery is increased steeply.