个人简介
Ling 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 joined School of Pharmaceutical Sciences, Tsinghua University as an assistant professor in 2021. His research interest lies at the interface of chemistry and biology.
Education & Research Experiences
B.S. Univeristy of Science and Technology of China, 2012 Advisor: Prof. Yao Fu and Prof. Lei Liu (Tsinghua Univeristy)
Ph.D. The Scripps Research Institute, 2017 Advisor: Prof. Jin-Quan Yu
Brown-Coxe Postdoctoral Fellow, Yale School of Medicine, 2017 – 2019 Advisor: Prof. Alanna Schepartz and Prof. Derek Toomre
Postdoctoral Associate, Yale Univeristy, 2019 – 2021 Advisor: Prof. Craig Crews
Awards
“Thousand Young Talent” plan, 2020 Future faculty in chemistry symposium, Harvard Department of Chemistry, 2018
Brown-Coxe postdoctoral fellowship, Yale School of Medicine, 2018
National scholarship for outstanding self-financed Chinese student, 2017
IPMI Elemental graduate student award, 2016
Genentech graduate student symposium in chemical research, 2016
Excellent award in undergraduate research program scholarship, USTC, 2011
First prize in “Challenge Cup” national undergraduate academic competition, 2011
Outstanding award in “Challenge Cup” school finals, USTC, 2011
研究领域
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 in cancer therapeutics. 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. We will also develop photo-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”.
近期论文
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Q. Wang, Y. Song, S. Yuan, Y. Zhu, W. Wang and L. Chu* Prodrug activation by 4,4’-bipyridine-mediated aromatic nitro reduction. Nature Communications 2024, 15, 8643.
Y. Wang, S. Luo, H. Su, Z. Wang*, L. Chu* and C. Zhang* BL-918 activates PINK1/Parkin signaling pathway to ameliorate the progression of Parkinson’s disease. J. Biol. Chem. 2024, 300, 107543.
Y. Zhu†, X. Yan†, Y. Chi, B. Liu, W. Huang and L. Chu* Near-Infrared Light Controlled Protein Degradation by Photo-caged Lenalidomide and Pomalidomide. Bioorganic Chemistry 2024, 143, 107050.
Y. Hou , Z. Wang , P. Liu , X. Wei, Z. Zhang, S. Fan, L. Zhang, F. Han, Y. Song, L. Chu, C. Zhang* SMPDL3A is a cGAMP-degrading enzyme induced by LXR-mediated lipid metabolism to restrict cGAS-STING DNA sensing. Immunity 2023, 56, 2492-2507.
Z. Du, W. Wang, S. Luo, L. Zhang, S. Yuan, Y. Hei, Z. Bao, C. Chen, Y. Lin, and L. Chu* Self-Renewable Tag for Photostable Fluorescence Imaging of Proteins. J. Am. Chem. Soc. 2023, 145, 18968-18976.
K.T.G. Samarasinghe, E. An, M.A. Genuth, L. Chu, S.A. Holley, C.M. Crews, OligoTRAFTACs: A generalizable method for transcription factor degradation. RSC Chem. Biol. 2022, 3, 1144-1153.
J. Tyson, K. Hu, S. Zheng, P. Kidd, N. Dadina, L. Chu, D. Toomre, J. Bewersdorf, A. Schepartz, Extremely Bright, Near-IR Emitting Spontaneously Blinking Fluorophores Enable Ratiometric Multicolor Nanoscopy in Live Cells. ACS Cent. Sci. 2021, 7, 1419-1426.
M. J. Bond†, L. Chu†, D. A. Nalawansha, K. Li, C. Crews Targeted Degradation of Oncogenic KRASG12C by VHL-recruiting PROTACs. ACS Cent. Sci. 2020, 6, 1367-1375. (†equal contributions)
L. Chu, J. Tyson, J. Shaw, F. Rivera-Molina, A. Koleske, D. Toomre, and A. Schepartz Two-color nanoscopy of organelles for extended times with HIDE probes. Nat. Comm. 2020, 11, 4271.
Z. Jin†, L. Chu†, Y. Chen, and J.-Q. Yu Pd-Catalyzed Remote meta-C–H Functionalization of Phenylacetic Acids Using a Pyridine Template. Org. Lett. 2018, 20, 425-428. (†equal contributions)
E. Plata, D. E. Hill, B. E. Haines, D. G. Musaev, L. Chu, D. P. Hickey, M. S. Sigman, J.-Q. Yu and D. G. Blackmond A Role for Pd(IV) in Catalytic Enantioselective C–H Functionalization with Monoprotected Amino Acid Ligands under Mild Conditions. J. Am. Chem. Soc. 2017, 139, 9238-9245.
K. J. Xiao, L. Chu, G. Chen, J.-Q. Yu Kinetic resolution of benzylamines via Palladium(II)-catalyzed C–H cross-coupling. J. Am. Chem. Soc.2016, 138, 7796-7780.
K. J. Xiao, L. Chu, J.-Q. Yu Enantioselective C–H olefination via kinetic resolution. Angew. Chem. Int. Ed. 2016, 55, 2856-2860.
L. Chu, M. Shang, K. Tanaka, Q. Chen, N. Pissarnitski, E. Streckfuss, and J.-Q. Yu Remote meta-C–H activation using a pyridine-based template: achieving site-selectivity via the recognition of distance and geometry. ACS Cent. Sci. 2015, 1, 394-399.
D. Zhu, G. Yang, J. He, L. Chu, G. Chen, W. Gong, K. Chen, M. D. Eastgate, J.-Q. Yu Ligand-promoted ortho-C−H amination with Pd catalysts. Angew. Chem., Int. Ed. 2015, 54, 2497-2500.
L. Chu, K. -J. Xiao, J.-Q. Yu Room-temperature enantioselective C–H iodination via kinetic resolution. Science2014, 346, 451-455.
K. S. L. Chan, M. Wasa, L. Chu, B. N. Laforteza, M. Miura, J.-Q. Yu Ligand-enabled cross-coupling of C(sp3)–H bonds with arylboron reagents via Pd(II)/Pd(0) catalysis. Nature Chem. 2014, 6, 146-150.
L. Chu, X. -C. Wang, C. E. Moore, A. L. Rheingold, J.-Q. Yu Pd-catalyzed enantioselective C–H Iodination: asymmetric synthesis of chiral diarylmethylamines. J. Am. Chem. Soc. 2013, 135, 16344-16347.
R. Shang, Z. Huang, L. Chu, Y. Fu, L. Liu Palladium-catalyzed decarboxylative coupling of potassium nitrophenyl acetates with aryl halides. Org. Lett. 2011, 13, 4240-4243.
R. Shang, D. S. Ji, L. Chu, Y. Fu, L. Liu Synthesis of α-aryl nitriles through palladium-catalyzed decarboxylative coupling of cyanoacetate salts with aryl halides and triflates. Angew. Chem., Int. Ed. 2011, 50, 4470-4474.
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