The research area of the MCCB laboratory covers from organic synthesis to chemical biology. As an educational platform, the students belonging to the MCCB laboratory are trained to gain profound knowledges on organic chemistry, reaction mechanisms, synthetic strategy, biochemistry, and molecular biology. In addition, updated information on the researches about total synthesis of complex molecules, medicinal chemistry, as well as chemical biology will be discussed within the group. 

Currently, the research of the MCCB laboratory is primarily focused on two themes:
(1) Development of new targeted protein degradation (TPD) strategies
(2) Establishment of innovative DNA-encoded library (DEL) screening technologies

Our ultimate goal is to discover effective therapeutic agents by harnessing the full potential of our in-house platform technologies. Currently, our research efforts are directed toward two major disease areas: cancer and mycobacterial infections—both of which represent significant and persistent challenges in modern medicine. Through our innovative approaches, we aspire to make meaningful breakthroughs that can overcome the limitations of existing therapies. Ultimately, we hope that our work will contribute to advancing human health and well-being on a global scale.

Edited in July, 2025

Targeted Protein Degradation is a transformative approach in drug discovery that is reshaping the landscape of medicinal chemistry. Unlike traditional small molecule therapeutics, which function primarily by inhibiting the enzymatic activity or blocking the interaction interfaces of target proteins, TPD aims to eliminate disease-causing proteins altogether from cells by harnessing the cell’s own protein degradation machinery.

The core strategy of TPD involves small molecules that recruit a target protein to an intracellular degradation system, such as the ubiquitin-proteasome pathway or the autophagy-lysosome system. These bifunctional or chimeric molecules—commonly referred to as "degraders"—do not merely bind to the protein of interest (POI) but induce its proximity to protein degradation machinery, leading to its selective and catalytic destruction.

A prominent example is the PROTAC (PROteolysis-TArgeting Chimera), a heterobifunctional molecule consisting of two ligands joined by a chemical linker. One ligand binds to the POI, while the other engages an E3 ubiquitin ligase. Upon simultaneous binding, the POI is ubiquitinated by the E3 ligase, marking it for recognition and degradation by the 26S proteasome. This process is catalytic in nature, meaning a single PROTAC molecule can induce degradation of multiple POI molecules, thereby offering potential for sustained pharmacological effects even after compound clearance.

Compared to traditional small-molecule inhibitors, TPD agents offer several key advantages, including access to a broader range of targets—such as non-enzymatic or scaffolding proteins—a catalytic mode of action that enables substoichiometric activity, and the potential to overcome drug resistance by eliminating the target protein entirely. The discovery of novel TPD agents and the development of innovative degradation platforms are areas of active research across medicinal chemistry, chemical biology, and translational drug discovery. The core mission of the MCCB Laboratory is to design and establish unprecedented TPD platforms and to leverage them for the discovery of effective, mechanism-driven therapeutics targeting cancer and infectious diseases. 

The followings are on-going TPD projects:

(1) Establishing a platform for unbiased screening of molecular glue degraders ("GlueMap", 김승우, 김수민)
(2) Development of a probe for characterizing lysosome-targeting ligands (김지원, 김현태)
(3) Development of TPD technology targeting mycobacteria ("PupTAG", "Pup-Anchor", 김수민, 이은서, 구동헌) 

One of the major bottlenecks in small molecule-based drug discovery is the identification of promising hit compounds. This process typically involves the generation of chemical libraries through synthetic chemistry and subsequent high-throughput screening to identify candidates with desirable activity profiles. Although this approach has been the cornerstone of drug discovery for decades, it remains costly, labor-intensive, and time-consuming, often requiring substantial long-term investment for each campaign. These challenges have driven the demand for innovative technologies that can streamline hit identification and accelerate early-stage drug discovery. 

DNA-encoded library (DEL) screening is one of the leading technologies in that regard. This approach harnesses the ultrasensitivity of polymerase chain reaction (PCR) and the high-throughput capacity of next-generation sequencing (NGS) to enable rapid and efficient identification of hit compounds from vast chemical libraries using only minute quantities—often at the picomole scale. Structurally, DEL compounds consist of small molecules covalently linked to DNA tags, which encode the synthetic history and identity of the chemical moiety. In a typical DEL screening workflow, libraries are incubated with an immobilized target protein to enrich binders through affinity selection, followed by PCR amplification and sequencing of the associated DNA tags to identify active compounds. While powerful, this method has inherent limitations—chief among them the requirement for soluble, immobilizable protein targets. As a result, many therapeutically relevant targets, such as membrane proteins, intrinsically disordered proteins, and protein–protein interfaces that are difficult to isolate or stabilize, remain largely inaccessible to conventional DEL screening strategies. 

To overcome such inherent limitations of conventional DEL screening, our strategy involves the incorporation of crosslinking moieties into DEL compounds to induce covalent bond formation between hit compounds and their target proteins. This approach enables the capture and identification of ligands with weak or moderate affinities, thereby enhancing enrichment efficiency and hit fidelity. Moreover, covalent crosslinking facilitates the screening of target proteins in their native environments—such as within membrane fractions or cell lysates—significantly expanding the range of protein targets accessible to DEL-based discovery.

The following is on-going DEL project:

(1) Establishing a screening platform using degenerate photocrossliking DNA-encoded library ("dpX-DEL", 김민재, 김아진)