Dr. Li Tan has been working on small molecule modulators and medicinal chemical biology over a decade. As a postdoc research fellow, he had successfully developed targeted inhibitors of important kinases, e.g., FGFRs, JAK3, TAK1 and DDR1. These kinases are either established or potential therapeutic targets; however, next-generation inhibitors selectively targeting them or their mutants are always in demand. Utilizing structure-based design, he had successfully developed covalent or type-II inhibitors targeting these kinases. His discoveries also revealed the novel binding modes of these inhibitors with co-crystal structure determination, and preliminarily assessed the pharmacological perturbation of these targets in disease’s contexts. By providing targeted chemical probes and preclinic drug candidates, these works have significantly advanced related biomedical researches and drug discovery.

In his independent lab at IRCBC, 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.