About the PI

Ling Chu was born and raised in Hefei, Anhui, China. He received a B.S. degree in Chemistry from the University of Science and Technology of China in 2012. He completed his Ph.D. study at the Scripps Research Institute, where he conducted research with Prof. Jin-Quan Yu on the development of Palladium-catalyzed C-H activation reactions. After completing his Ph.D. in 2017, he switched his research field to chemical biology and worked with Prof. Alanna Schepartz and Prof. Derek Toomre as a Brown-Coxe postdoctoral fellow at Yale School of Medicine. In the Schepartz/Toomre lab, he developed new chemical biology tools for two-color long-time lapse live-cell super-resolution imaging. He then joined Prof. Craig Crews’ lab in 2019 as a postdoctoral associate, where he led the development of first PROTAC capable of degrading oncogenic KRASG12C. Ling will join School of Pharmaceutical Sciences, Tsinghua University as an assistant professor in 2021. His research interest lies at the interface of chemistry and biology.

Website: chu-lab.org
Email: chu_lab@126.com

About the research

New chemical biology tools to explore the beyond-rule-of-5 drug space

There is an increasing need to pursuit less druggable targets that offer high potential for the development of new therapeutic agents and may require beyond-rule-of-5 (bRo5) molecules in order to take advantage of these opportunities. Nevertheless, bRo5 chemical space remains relatively unexplored, most likely due to the perceived non-oral properties, increased complexity of compounds in this space and the synthetic chemistry challenges associated with its navigation. There is a pressing need to develop new technologies for the discovery and oral delivery of bRo5 drugs. We will develop new chemical biology approaches that enable phenotypic screening of large, de novo bRo5 compound libraries inside living cells. Such efforts could potentially yield novel hits for “undruggable” targets. The strategies used here will be further pursued for applications in oral delivery of bRo5 compounds.

Affecting protein stability as a new strategy to target KRAS

The Kirsten rat sarcoma viral oncogene homologue (KRAS) gene is one of the most frequently mutated oncogenes in cancer. KRAS is mutated in ～30% of human cancers and is one of the most sought-after targets for pharmacological modulation. Despite its well-recognized importance in cancer malignancy, continuous efforts in the past three decades failed to develop approved therapies for KRAS mutant cancer. Recent efforts in direct targeting KRASG12C have resulted in small molecule inhibitors that showed great promise in early clinical trials. However, G12C mutant only represents a small percentage of patients with oncogenic KRAS mutations. To explore a general strategy to target KRAS, we will combine chemical screen and genetic screen to identify small molecules and genes that can destabilize KRAS across different mutant KRAS cell lines. Results from these screens will provide novel therapeutic leads and mechanistic insights of KRAS degradation pathway. Leveraging these findings, we hope to develop next-gen small molecule therapeutics for the treatment of KRAS mutant cancer.

New tools for live-cell protein labeling and super-resolution imaging

Proteins are the essential components in cell function. To understand the function of proteins in living cells, it is important to know the properties of proteins in the temporal and spatial context of the cell. Currently, live-cell protein labeling and imaging technologies have several limitations: 1) Widely adopted tools for live-cell protein labeling have a large size (20-30kDa), giving rise to concerns that they may interfere with protein folding, trafficking, activity, and interactions; 2) Fluorescence proteins or small molecule dyes bleach quickly under super-resolution imaging conditions, thus prevent long-term protein imaging. To solve these problems, we will develop short peptide tags for site-specific protein labeling in live cells. Such tags contain only a few amino acids and will have minimal perturbation of protein function in live cells. We will also develop bleaching-resistant live cell protein imaging tools that allow biologists to visualize the dynamics of proteins at the nanoscopy level (resolution<50 nm) with unlimited “photon budget”.

Training

We are an interdisciplinary research group working at the interface of chemistry and biology. Students in the lab will receive multidisciplinary training in experimental techniques ranging from synthetic chemistry to fluorescence microscopy to cellular studies. Representative skill sets in the group are given below. Chemical tools: organic synthesis, catalysts, medicinal chemistry, peptide synthesis Cell culture: mammalian cell lines, primary cell cultures Cell imaging: Confocal microscopy, STED, single-molecule microscopy, flow cytometry Molecular biology: Cloning, PCR, CRISPR Biochemistry: Protein purification, western blotting

About the job

We are actively recruiting. If you are passionate about chemical biology and drug discovery, come join us! Don’t hesitate to reach out to Dr. Chu at chu_lab@126.com

Postdoc positions in biology

Candidates should hold a PhD degree in cell biology, biochemistry, chemical biology, pharmacology or related fields. Experiences in phenotypic high-throughput assay or CRISPR screen are preferred but not required. If you are interested in joining the lab, please send your CV, research summary, and contact information of three referees to Dr. Chu at chu_lab@126.com.

Postdoc positions in chemistry

Candidates should hold a PhD degree in organic chemistry, medicinal chemistry or related fields. Experiences in transition-metal catalysts are preferred but not required. If you are interested in joining the lab, please send your CV, research summary, and contact information of three referees to Dr. Chu at chu_lab@126.com.

Research assistants/Technicians

Candidates should hold an MS or BS degree in chemistry or biology. If you are interested in joining the lab, please send your CV and contact information of three referees to Dr. Chu at chu_lab@126.com.

Competitive salaries will be provided for qualified applicants.

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