Research

Protein Modulating Drug Discovery

Protein Modulating Drug Examples

PROTAC Discovery

Proteolysis Targeting Chimeras (PROTACs) represent a paradigm shift in drug development. Unlike traditional small molecules that inhibit proteins, PROTACs harness the cell's own machinery to selectively degrade target proteins. This innovative approach opens new avenues for treating diseases that were once considered challenging to address.

At the forefront of modern pharmacology, PROTACs hold the promise of precise and potent therapeutic interventions. By leveraging the principles of targeted protein degradation, we aim to revolutionize the way we combat diseases, including those driven by undruggable targets.

Our lab is dedicated to advancing PROTAC discovery through cutting-edge design, synthesis, and validation strategies. We believe that collaboration and innovation are fundamental to unlocking the full potential of this transformative technology. Together, we're poised to shape the future of medicine through the development of next-generation therapeutics.

Introduction of PROTAC (Korean)

Advanced PROTAC Discovery: Bridged PROTAC

Bridged Proteolysis Targeting Chimera (PROTAC) Enables Degradation of Undruggable TargetsProteolysis Targeting Chimeras (PROTACs) are attractive therapeutic modalities for degrading disease-causing proteins. While many PROTACs have been developed for numerous protein targets, current small-molecule PROTAC approaches cannot target undruggable proteins that do not have small-molecule binders. Here, we present a novel PROTAC approach, termed bridged PROTAC, which utilizes a small-molecule binder of the target protein’s binding partner to recruit the protein complex into close proximity with an E3 ubiquitin ligase to target undruggable proteins. Applying this bridged PROTAC strategy, we discovered MS28, the first-in-class degrader of cyclin D1, which lacks a small-molecule binder. MS28 effectively degrades cyclin D1, with faster degradation kinetics and superior degradation efficiency than CDK4/6, through recruiting the CDK4/6-cyclin D1 complex to the von Hippel–Lindau E3 ligase. MS28 also suppressed the proliferation of cancer cells more effectively than CDK4/6 inhibitors and degraders. Altogether, the bridged PROTAC strategy could provide a generalizable platform for targeting undruggable proteins.

Reference: J. Am. Chem. Soc. 2022, 144, 49, 22622–22632.

Introduction of Bridged PROTAC (Korean)

Covalent Inhibitor Discovery

Covalent inhibitors represent a powerful class of compounds in the realm of drug discovery. Unlike traditional non-covalent inhibitors, covalent compounds form a durable bond with their target proteins, offering enhanced selectivity and prolonged pharmacological effects. This distinctive mode of action has garnered significant interest in recent years.

At our lab, we are at the forefront of covalent inhibitor research, dedicated to pioneering innovative strategies for the design and development of these promising therapeutics. Through meticulous molecular design and rigorous validation, we aim to create tailored covalent inhibitors targeting a diverse range of disease-associated proteins.

Our collaborative approach, combining expertise in chemistry, biology, and computational methods, allows us to navigate the complexities of covalent binding, ensuring the precision and efficacy of our inhibitors. Together, we are shaping the future of medicine with the next generation of covalent therapeutics.

Discovery of the First-in-Class G9a/GLP Covalent InhibitorsThe highly homologous protein lysine methyltransferases G9a and GLP, which catalyze mono- and dimethylation of histone H3 lysine 9 (H3K9), have been implicated in various human diseases. To investigate functions of G9a and GLP in human diseases, we and others reported several noncovalent reversible small-molecule inhibitors of G9a and GLP. Here, we report the discovery of the first-in-class G9a/GLP covalent irreversible inhibitors, 1 and 8 (MS8511), by targeting a cysteine residue at the substrate binding site. We characterized these covalent inhibitors in enzymatic, mass spectrometry based and cellular assays and using X-ray crystallography. Compared to the noncovalent G9a/GLP inhibitor UNC0642, covalent inhibitor 8 displayed improved potency in enzymatic and cellular assays. Interestingly, compound 8 also displayed potential kinetic preference for covalently modifying G9a over GLP. Collectively, compound 8 could be a useful chemical tool for studying the functional roles of G9a and GLP by covalently modifying and inhibiting these methyltransferases.

Reference: J. Med. Chem. 2022, 65, 15, 10506–10522

Discovery of Post-Translational Modifications (PTM) Modulator

In the end, our lab aims to broaden the scope of heterobifunctional technology for fine-tuning the PTM status of disease-related proteins we target. Leveraging our expertise in PROTACs, our team will engineer a heterobifunctional compound capable of commandeering the PTM process of the designated protein. This innovative molecule holds the potential to usher in a new era, allowing for a comprehensive exploration of the intricate functions associated with the specific PTM status of our target protein.

Examples for PTM modulators

1) Deubiquitination

2) Acetylation

3) Phosphorylation

4) Dephosphorylation