The research goals of Dr. Tan include developing novel chemical targeting strategies and modalities, including targeted covalent inhibitors, PROTACs and molecular glues. He seeks to develop new strategies to modulate not only specific protein phosphorylation, but also ubiquitination and protein aggregates. Utilizing an arsenous warhead and structure-guided design, he has developed the first organoarsenic covalent inhibitors targeting CDK12/13 or PKM2, with considerably more favorable pharmacokinetic properties compared to the reported ones. In addition, using high-throughput screening and structure-guided design, he has developed a potent and selective inhibitor of SARS-CoV-2 PLpro, a DUB-like protease fundamental for viral replication. Based on PROTAC technologies and chemoproteomic approaches, he and collaborators have developed multi-targeted kinase-PROTACs which were capable to induce the degradation of multiple therapeutic targets, such as BTK, ALK, FLT3 and CDK12, providing rational design basis for successful development of selective kinase PROTACs in future. In addition, he has developed small molecule inhibitors targeting a novel allosteric pocket of RIPK1, as well as best-in-class RIPK1 inhibitor candidates that are currently under preclinical evaluation and licensing. These studies not only validated useful covalent warheads, prototypical probes and proof-of-concepts, but also provided promising strategies and leads for drug discovery campaign against cancer, inflammation, COVID-19 or neurodegenerative diseases.

2004.9 - 2009.7   Ph.D. in Organic Chemistry

Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences

Advisor: Dr. Dawei Ma

Research experience: Total synthesis of natural products with complex

structures and biological functions

Honor: Roche Creative Chemistry Award (2008)

2000.9 - 2004.7   B.S. in Chemistry

Nanjing University, Nanjing

   

2016.6 – Now     Principle Investigator

Interdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences

2015.4 – 2016.5   Research Scientist

Cancer Biology, Dana-Farber Cancer Institute

2010.4 – 2015.3   Postdoctoral Research Fellow

Cancer Biology, Dana-Farber Cancer Institute

And Department of Biochemistry and Molecular Pharmacy, Harvard Medical School

Research experience: Structure-based design and characterization of

novel small molecule inhibitors modulating diseases 

2009.7 - 2009.12  Research Fellow

Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences

   

1.      Qin, Y.; Li, D.; Qi, C.; Xiang, H.; Meng, H.; Liu, J.; Zhou, S.; Gong, X.; Li, Y.; Xu, G.; Zu, R.; Xie, H.; Xu, Y.; Xu, G.; Zhang, Z.; Chen, S.; Pan, L.; Li, Y.*; Tan, L.*, Structure-based development of potent and selective type-II kinase inhibitors of RIPK1. Acta Pharm Sin B 2024, 14 (1), 319-334.

2.      Shen, P.; Ye, K.; Xiang, H.; Zhang, Z.; He, Q.; Zhang, X.; Cai, M.C.; Chen, J.; Sun, Y.; Lin, L.; Qi, C; Zhang, M.; Cheung, L.W.T.; Shi, T.; Yin, X.; Li, Y.; Di, W.*; Zang, R.*; Tan, L.*; Zhuang, G.*, Therapeutic targeting of CPSF3-dependent transcriptional termination in ovarian cancer. Sci Adv 2023, 9(47):eadj0123.

3.      Wang, J.; Zhou, S.; Cheng, Y.; Cheng, L.; Qin, Y.; Zhang, Z.; Bi, A.; Xiang, H.; He, X.; Tian, X.; Liu, W.; Zhang, J.; Peng, C.; Zhu, Z.; Huang, M.; Li, Y.*; Zhuang, G.*; Tan, L.*, Selective Covalent Targeting of Pyruvate Kinase M2 Using Arsenous Warheads. J Med Chem 2023, 66 (4), 2608-2621.

4.      Cheng, L.; Zhou, S.; Zhou, S.; Shi, K.; Cheng, Y.; Cai, M. C.; Ye, K.; Lin, L.; Zhang, Z.; Jia, C.; Xiang, H.; Zang, J.; Zhang, M.; Yin, X.; Li, Y.*; Di, W.*; Zhuang, G.*; Tan, L.*, Dual Inhibition of CDK12/CDK13 Targets Both Tumor and Immune Cells in Ovarian Cancer. Cancer Res 2022, 82 (19), 3588-3602.

5.      Tan, L.; Shan, H.; Han, C.; Zhang, Z.; Shen, J.; Zhang, X.; Xiang, H.; Lu, K.; Qi, C.; Li, Y.; Zhuang, G.*; Chen, G.*; Tan, L.*, Discovery of Potent OTUB1/USP8 Dual Inhibitors Targeting Proteostasis in Non-Small-Cell Lung Cancer. J Med Chem 2022, 65 (20), 13645-13659.

6.      Lin, L.; Shi, K.; Zhou, S.; Cai, M. C.; Zhang, C.; Sun, Y.; Zang, J.; Cheng, L.; Ye, K.; Ma, P.; Shen, P.; Zhang, M.; Cheng, Y.; Qi, C.; Li, Y.; Yin, X.; Zheng, Y.; Tan, L.*; Zhuang, G.*; Zang, R.*, SOX17 and PAX8 constitute an actionable lineage-survival transcriptional complex in ovarian cancer. Oncogene 2022, 41 (12), 1767-1779.

7.      Shan, H.; Liu, J.; Shen, J.; Dai, J.; Xu, G.; Lu, K.; Han, C.; Wang, Y.; Xu, X.; Tong, Y.; Xiang, H.; Ai, Z.; Zhuang, G.; Hu, J.; Zhang, Z.*; Li, Y.*; Pan, L.*; Tan, L.*, Development of potent and selective inhibitors targeting the papain-like protease of SARS-CoV-2. Cell Chem Biol 2021, 28 (6), 855-865 e9.

8.      Meng, H.; Wu, G.; Zhao, X.; Wang, A.; Li, D.; Tong, Y.; Jin, T.; Cao, Y.; Shan, B.; Hu, S.; Li, Y.; Pan, L.; Tian, X.; Wu, P.; Peng, C.; Yuan, J.; Li, G.*; Tan, L.*; Wang, Z.*; Li, Y.*, Discovery of a cooperative mode of inhibiting RIPK1 kinase. Cell Discov 2021, 7 (1), 41.

9.      Huang, H. T.; Dobrovolsky, D.; Paulk, J.; Yang, G.; Weisberg, E. L.; Doctor, Z. M.; Buckley, D. L.; Cho, J. H.; Ko, E.; Jang, J.; Shi, K.; Choi, H. G.; Griffin, J. D.; Li, Y.; Treon, S. P.; Fischer, E. S.; Bradner, J. E.; Tan, L.*; Gray, N. S.*, A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader. Cell Chem Biol 2018, 25 (1), 88-99 e6.