Drug Discovery and Translational Research: (Organic Synthesis and Medicinal Chemistry) + (Assay Development and Mechanism of Action of Drugs) + (Novel Delivery Methods)
Core Focus Areas
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Drug Discovery
Drug discovery is highly interdisciplinary and requires a broad range of skill sets. In addition to the design and synthesis of drug candidates, we develop various cell-based and biochemical assays to evaluate the pharmacological properties of the drug candidates such as potency, selectivity, and stability. We also design assays to study the detailed cellular mechanisms of action of novel small molecules we developed such as how they induce the ubiquitination, degradation, and internalization of protein targets in cells. In addition, we also develop delivery methods for the therapeutic agents we prepared through the discovery of novel ligands for receptors and transporters.
a) We develop small molecules that can selectively remove disease-causing proteins in cells and animal models. These small molecules can be used as probes to knockdown proteins and therapeutics to treat human diseases. We have developed cellular active degraders for HDAC6 (ACS Med. Chem. Lett. 2020, Link; J. Med. Chem. 2019, Link; Bioorg. Med. Chem. Lett. 2018, Link.), MDM2 (Eur. J. Med. Chem. 2019, Link), ER (ACS Chem. Biol. 2020, Link.), and many other disease-causing proteins by recruiting CRBN and VHL E3 uiquitin ligases. We also develop new biological assays to test the activity and study the mechanism of action of our degraders (e.g. Cell Chem. Biol. 2020, 27, 866-876. Link.). Here is a link to a story with a video that illustrates how degrader works.
b) We develop small molecule ligands for carbohydrate-binding proteins that are located on the outer membrane. These membrane proteins are essential for cell-cell communications and many diseases, such as cancers and vascular diseases. Small molecule ligands for carbohydrate-binding proteins can be used as either therapeutics or drug delivery reagents.
Visit Degrader Digest for animations, updates, and events about protein degradation.
Medicinal Chemistry and Organic Synthesis
We are interested in developing novel reactions for the synthesis of carbo- and heterocycles that are present in diverse bioactive compounds. These reactions can be used for the optimization of pharmacological properties of small molecules such as potency, selectivity, stability, and solubility.
We are interested in developing novel enabling chemistry platforms that can accelerate the generation of large small molecule libraries.
We are also interested in advancing glycoscience by streamlining the synthesis of carbohydrates through the development of novel technologies (e.g. site-selective functionalization, de novo synthesis of bacterial sugars, automated synthesis, electrochemical synthesis, etc.). The carbohydrat
Chemical Biology and Mechanism of Action of Bioactive Compounds
We are interested in dissecting the complex biological pathways by novel small molecule probes. We are currently developing small molecules that can selectively modulate protein stability and epigenetic markers. For example, we have developed small molecules that can selectively downregulate PCSK9 proteins which may have the potential for treating hyperlipidemia. We have also developed small molecules that can selectively degrade estrogen receptors, which may have the potential for treating certain types of breast cancers. We employ a variety of chemical and biological tools to study the detailed mechanism of action of bioactive compounds.
Green Chemistry
We developed a series of water-soluble iridium catalysts, which have been used in several other laboratories. 1) “Iridium-catalyzed highly efficient chemoselective reduction of aldehydes in water using formic acid as the hydrogen source.” Yang, Z.; Zhu, Z.; Luo, R.; Qiu, X.; Liu, J.-L.; Yang, J.-K.; and Tang W.* Green Chem. 2017, 19, 3296-3301. Link. 2) “Harnessing the Reactivity of Iridium Hydrides by Air: Iridium-Catalyzed Oxidation of Aldehydes to Acids in Water.” Yang, Z.; Luo, R.; Zhu, Z.; Yang, X.; and Tang W.* Organometallics 2017, 36, 4095–4098. Link. 3) “Iridium-catalyzed efficient reduction of ketones in water with formic acid as hydride donor at low catalyst loading” Liu, J.; Yang, S.; Tang, W.; Yang, Z.;* and Xu, J.* Green Chem. 2018, 20, 2118-2124. Link. 4) “Iridium-Catalyzed Highly Efficient and Site-Selective Deoxygenation of Alcohols” Yang, S.; Tang. W.; Yang, Z.;* and Xu, J.* ACS Cat. 2018, 8, 9320-9326. Link. 5) “Highly pH-Dependent Chemoselective Transfer Hydrogenation of α,β-Unsaturated Aldehydes in Water” Luo, N.; Liao, J.; Ouyang, L.; Wen, H.; Liu, J.; Tang, W.; Luo, R.* Organometallics 2019, 38, 3025–3031. Link. 6) “Iridium-catalysed highly selective reduction-elimination of steroidal 4-en-3-ones to 3,5-dienes in water ” Li, J.; Tang, W.; Ren, D.; Xu, J.*; Yang, Y.* Green Chem. 2019, 21, 2088-2094. Link. 7) “Highly Selective Hydroxylation and Alkoxylation of Silanes: One-Pot Silane Oxidation and Reduction of Aldehydes/Ketones” Luo, N.; ; Liao, J.; Ouyang, L.; Wen, H.; Zhong, Y.; Liu, J.; Tang, W.; Luo, R.* Organometallics 2020, 39, 165-171. Link. 8) “Synthesis of Lactams via Ir-Catalyzed C-H Amidation Involving Ir-Nitrene Intermediates” Liu, J.*; Ye, W.; Wang, S.; Zheng, J.; Tang, W.; Li, X.* J. Org. Chem. 2020, 85, 4430-4440. Link.