Faculty | Xuebin LIAO, Ph. D
Xuebin Liao, PI
Tenure-Track Associate Professor, School of Pharmaceutical Science, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University. Prof. Xuebin Liao obtained his B.S. degree from Peking University in 1995. Then he did his Ph.D work on natural product synthesis with Prof. James M. Cook at the University of Wisconsin at Milwaukee from 1998-2004. After that, from 2005-2008, he was a postdoctoral associate with Prof. John F. Hartwig at Yale and later at UIUC. In 2009, he held a position of Research Investigator I at GNF (the Genomics Institute of the Novartis Research Foundation). At GNF, his research was centered on discovering new drug candidates for pharmaceutical optimization. In September of 2012, he joined the Department of Pharmacology and Pharmaceutical Science, School of Medicine, Tsinghua University. He won the “Roche Chinese Investigator Award” in 2018 and “The Thieme Chemistry Journals Award” in 2020.
Research Interests
(1) The molecular mechanisms that regulate functionality of MAP4K family kinases (particularly for HPK1 and GLK) and structure-based drug design for inhibitors of MAP4K family kinases.
(2) Epigenetic regulation on cancer immunotherapy;(3) TLR-related innate immune functions and discover novel TLR7 or 8 agonists and TLR7/8 dual agonists;
(4) Natural products-oriented synthesis and new synthetic method development.
Major scientific contributions
One of major interests in Prof. Liao's group is to develop a variety of small molecule tool compounds to study innate immunity on anti-cancer activities. Cancer immunotherapy includes treatments that work in different ways. Some treatments involve boosting of the body's immune system in a very general way. Others help train the immune system to attack cancer cells specifically. Among these treatments, the blockade of immune checkpoints approach and the adoptive cell transfer such as CAR-T therapy have held a lot of promise as cancer treatment. However, recent studies suggest that immune checkpoint blockade such as PD-1 pathway blockade as a monotherapy will only succeed in the setting of pre-existing antitumor immune response in such patients. CAR-T monotherapy also exhibited very poor efficacies for the treatments of solid tumors during the pre-clinic studies. To expand efficacy of monotherapy, the combined therapies such as PD-1 monoclonal antibody with TLRs agonists or CAR-T with other immune modulators were extensively attempted in Prof. Liao’s lab. The “synergistic effects” were observed and the detailed mechanistic studies are ongoing.
1) Completed several total syntheses of biologically active indole alkaloids based on the novel methods developed in our group; Developed some useful methods for medicinal chemistry, for example: a nickel-catalyzed methylation of aryl halides with deuterated methyl iodide was recently developed in our lab.
2) With our newly developed TLR7/8 small molecule dual agonists and HPK1 inhibitors, different combination studies showed “synergistic effects”.
Selected Achievements
1. HPK1 promotes T cell dysfunction via NFκB-Blimp1 activation. HPK1 is an attractive druggable target to improve immunotherapies by applying MAP4K1KO CAR-T cells, a small-molecule HPK1 inhibitor, and a proteolysis targeting chimera (PROTAC). In addition, various toxicological, pharmacological and CMC studies for our novel HPK1 inhibitor have been completed. Furthermore, the clinical trial was conducted in Xijing Hospital (NCT04037566) for HPK1 gene edited CAR T cell therapy. This investigational trial has demonstrated the safety of HPK1 gene editing and preliminary efficacy, and this study will expand its clinical applicability.
2. A KDM5A gene signature correlated with KDM5A expression and could potentially serve as a marker of response to anti–PD-1 immunotherapy. Furthermore, we developed the bifunctional agents that enhance both KDM5A and TLR activity warrant investigation as combination therapies with ICB agents.
3. TLR7 agonist imiquimod has been approved by FDA for the treatment of verruca acuminata. However, other TLR7 and 8 agonists have not yet advanced into clinical application, mainly due to the deficiency of therapeutic efficacy of existing agonists or immune-associated adverse reactions (irAEs) induced by activation of the target itself. We designed a series of pyrido[3,2-d]pyrimidine-based potent TLR7/8 dual agonists that held great potential as single agents or in combination with PD-1/PD-L1blockade for cancer immunotherapy.
Honors and Awards
Tsinghua-Janssen Investigator Award (2013-2015)
Roche Chinese Investigator Award (2018)
The Thieme Chemistry Journals Award (2020)
Roche Chinese Investigator Award (2018)
The Thieme Chemistry Journals Award (2020)
Selected Publications
1. “Structure-Based Drug Design of Highly Potent Toll-Like Receptor 7/8 dual Agonists for Cancer Immunotherapy”, Wang, Z.; # Gao, Y.; # He, L.; # Sun, S.; Xia, T.; Hu, L.; Yao, L.; Wang, L.; Li, D.; Shi, H.; Liao, X. * J. Med. Chem. 2021, ASAP.
2. “Tumor Immunological Phenotype Signature-based High Throughput Screening for the Discovery of Combination Immunotherapy Compounds”, Wang, H.; Li, S.; Wang, Q.; Jin, Z.; Shao, W.; Gao, Y.; Li, L.; Lin, K.; Zhu, L.; Wang, H.; Liao, X.; Wang, D.* Sci Adv. 2021, 7(4), eabd7851.
3. “Recent Progress in Radical Decarboxylative Functionalizations Enabled by Transition Metal (Ni, Cu, Fe, Co or Cr) Catalysis”, Chen, H.; Liu, Y.; * Liao, X. * Synthesis 2021, 53, 1–29.
4. “Hematopoietic progenitor kinase1 (HPK1) mediates T cell dysfunction and is a druggable target for T-cell based immunotherapies”, Si, J.; # Shi, X.; # Sun, S.; # Zou, B.; # Li, Y.; An, D.; Lin, X.; Gao, Y.; Long, F.; Pang, B.; Liu, X.; Liu, T.; Chi, W.; Chen, L.; Dimitrov , D. S.; Sun, Y.; Du, X.; Yin, W.; Gao, G.; Min, J.; Wei, L.; * Liao, X.* Cancer Cell 2020, 38, 551.
5. “Enhancing KDM5A and TLR activity improves the response to immune checkpoint blockade”, Wang, L.;# Gao, Y.; # Zhang, G.; # Li, D.; # Wang, Z.; Zhang, J.; Hermida, L. C.; He, L.; Wang, Z.; Si, J.; Geng, S.; Ai, R.; Ning, F.; Cheng, C.; Deng, H.; Dimitrov, D. S.; Sun, Y.; Huang, Y.; Wang, D.; Hu, X.;* Wei, Z.; * Wang, W.;* Liao, X.* Sci Trans Med. 2020, 12, Issue 560, eaax2282.
6. “Neural regulation of humoral immune responses amenable to behavioral modulation”, Zhang, X.; Lei, B.; Yuan, Y.; Zhang, L.; Hu, L.; Jin, S.; Kang, B.; Liao, X.; Sun, W.; Xu, F.; Zhong, Y.; * Hu, J.; * Qi, H.* Nature 2020, 581, 204.
7. “Nickel-Catalyzed Cyanation of Aryl Halides and Hydrocyanation of Alkynes via C-CN Bond Cleavage and Cyano Transfer”, Chen, H.; Sun, S.; Liu, Y.; Liao, X. * ACS Catal. 2020, 10, 1397.
8. “A newly designed heterodiene and its application to construct six-membered heterocycles containing an N–O bond” Ji, W.; # Li, C.; # Chen, H.; Yu, Z.; * Liao, X.* Chem. Comm. 2019, 55, 12012.
9. “Nickel-Catalyzed Decarboxylative Alkenylation of Vinyl Triflates or Halides with Anhydrides”, Chen, H.; Sun, S.; Liao, X. * Org Lett 2019, 21, 3625.
10. “Nickel catalyzed decarboxylative alkylation of aryl triflates with anhydrides”, Chen, H.; Liao, X. * Tetrahedron 2019, 75, 4186. (Special issue in honor of Prof. John F Hartwig’s Tetrahedron Award)
11. “Nickel-Catalyzed Decarboxylative Alkylation of Aryl Iodides with Anhydrides”, Chen, H.; Hu, L.; Ji, W.; Yao, L.; Liao, X.*ACS Catal. 2018, 8, 10479.
12. “Enantioselective and Divergent Syntheses of Alstoscholarisines A, E and Their Enantiomers”, Hu, L.; # Li, Q.; # Yao, L.; # Chen, H.; Wang, X.; Liao, X.* Org. Lett. 2018, 20, 6202.
13. “Total synthesis of (±)minfiensine via a formal [3+2] cycloaddition”, Zhang, C.; Ji, W.; Liu, Y. A.; Song, C.*; Liao, X.* J. Nat. Prod. 2018, 81, 1065.
14. “Recent Progress in Methylation of (Hetero)Arenes”, Hu, L.; Liu, Y. A.; Liao, X.* Syn Lett. (SYNPACTS) 2018, 29, 375.
15. “Synthesis of Withasomnine and Pyrazole Derivatives via Intramolecular Dehydrogenative Cyclization, as well as Biological Evaluation of Withasomnine-based Scaffolds”, Xia, T.; Hu, Z.; Ji, W.; Zhang, S.; Shi, H.; Liu, C.; Pang, B.; Liu, G.; Liao, X.* Org. Chem. Fron. 2018, 5, 850.
16. “In situ generation of N-unsubstituted imines from alkyl azides and their applications for imine transfer via copper catalysis”, Hu, L.; Liu, Y. A.; Liao, X.* Sci. Adv. 2017, 3, e1700826 (Highlighted by Synform).
17. “Palladium-Catalyzed Cross-Coupling of Ethyl Bromodifluoroacetate with Aryl Bromides or Triflates and Cross-Coupling of Ethyl Bromofluoroacetate with Aryl Iodides”, Xia, T.; He, L.; Liu, Y. A.; Hartwig, J. F.*; Liao, X.* Org. Lett. 2017, 19, 2610.
18. “The Novel Toll-like Receptor 2 Agonist SUP3 Enhances Antigen Presentation and T cell Activation by Dendritic cells”, Guo, X.; Wu, N.; Shang, Y.; Liu, X.; Wu, T.; Zhou, Y.; Liu, X.; Huang, J.; Liao, X.*; Wu, L.* Front. Immunol. 2017, 8, 158/1-158/15.
19. “Transition-Metal-Free Synthesis of N-hydroxy Oxindoles via an Aza-Nazarov Type Reaction Involving Aza-Oxyallyl Cations”, Ji, W.; Liu, Y.; Liao, X.* Angew. Chem. Int. Ed. 2016, 55, 13286.
20. “Copper-Catalyzed 2, 2, 2-Trifluoroethylthiolation of Aryl Halides”, Chen, S.; Zhang, M.; Liao, X.*; Weng, Z.* J. Org. Chem. 2016, 81, 7993.
21. “Nickel-catalyzed Methylation of Aryl Halides with Deuterated Methyl Iodide”, Hu, L.; Liu, X.; Liao, X.* Angew. Chem. Int. Ed. 2016, 55, 9743.
22. “Access to the Pyrroloindoline Core via [3 + 2] Annulation as well as the Application in the Synthetic Approach to (±)-Minfiensine”, Ji, W.; Yao, L.; Liao, X.* Org. Lett. 2016, 18, 628.
23. “Enantioselective and Diastereoselective Azo-coupling/Iminium-Cyclization: A Unified Strategy for the Total Synthesis of (-)-Psychotriasine and (+)-Pestalazine B”, Li, Q.; Xia, T.; Yao, L.; Deng, H.*; Liao, X.* Chem. Sci. 2015, 6, 3599.
2. “Tumor Immunological Phenotype Signature-based High Throughput Screening for the Discovery of Combination Immunotherapy Compounds”, Wang, H.; Li, S.; Wang, Q.; Jin, Z.; Shao, W.; Gao, Y.; Li, L.; Lin, K.; Zhu, L.; Wang, H.; Liao, X.; Wang, D.* Sci Adv. 2021, 7(4), eabd7851.
3. “Recent Progress in Radical Decarboxylative Functionalizations Enabled by Transition Metal (Ni, Cu, Fe, Co or Cr) Catalysis”, Chen, H.; Liu, Y.; * Liao, X. * Synthesis 2021, 53, 1–29.
4. “Hematopoietic progenitor kinase1 (HPK1) mediates T cell dysfunction and is a druggable target for T-cell based immunotherapies”, Si, J.; # Shi, X.; # Sun, S.; # Zou, B.; # Li, Y.; An, D.; Lin, X.; Gao, Y.; Long, F.; Pang, B.; Liu, X.; Liu, T.; Chi, W.; Chen, L.; Dimitrov , D. S.; Sun, Y.; Du, X.; Yin, W.; Gao, G.; Min, J.; Wei, L.; * Liao, X.* Cancer Cell 2020, 38, 551.
5. “Enhancing KDM5A and TLR activity improves the response to immune checkpoint blockade”, Wang, L.;# Gao, Y.; # Zhang, G.; # Li, D.; # Wang, Z.; Zhang, J.; Hermida, L. C.; He, L.; Wang, Z.; Si, J.; Geng, S.; Ai, R.; Ning, F.; Cheng, C.; Deng, H.; Dimitrov, D. S.; Sun, Y.; Huang, Y.; Wang, D.; Hu, X.;* Wei, Z.; * Wang, W.;* Liao, X.* Sci Trans Med. 2020, 12, Issue 560, eaax2282.
6. “Neural regulation of humoral immune responses amenable to behavioral modulation”, Zhang, X.; Lei, B.; Yuan, Y.; Zhang, L.; Hu, L.; Jin, S.; Kang, B.; Liao, X.; Sun, W.; Xu, F.; Zhong, Y.; * Hu, J.; * Qi, H.* Nature 2020, 581, 204.
7. “Nickel-Catalyzed Cyanation of Aryl Halides and Hydrocyanation of Alkynes via C-CN Bond Cleavage and Cyano Transfer”, Chen, H.; Sun, S.; Liu, Y.; Liao, X. * ACS Catal. 2020, 10, 1397.
8. “A newly designed heterodiene and its application to construct six-membered heterocycles containing an N–O bond” Ji, W.; # Li, C.; # Chen, H.; Yu, Z.; * Liao, X.* Chem. Comm. 2019, 55, 12012.
9. “Nickel-Catalyzed Decarboxylative Alkenylation of Vinyl Triflates or Halides with Anhydrides”, Chen, H.; Sun, S.; Liao, X. * Org Lett 2019, 21, 3625.
10. “Nickel catalyzed decarboxylative alkylation of aryl triflates with anhydrides”, Chen, H.; Liao, X. * Tetrahedron 2019, 75, 4186. (Special issue in honor of Prof. John F Hartwig’s Tetrahedron Award)
11. “Nickel-Catalyzed Decarboxylative Alkylation of Aryl Iodides with Anhydrides”, Chen, H.; Hu, L.; Ji, W.; Yao, L.; Liao, X.*ACS Catal. 2018, 8, 10479.
12. “Enantioselective and Divergent Syntheses of Alstoscholarisines A, E and Their Enantiomers”, Hu, L.; # Li, Q.; # Yao, L.; # Chen, H.; Wang, X.; Liao, X.* Org. Lett. 2018, 20, 6202.
13. “Total synthesis of (±)minfiensine via a formal [3+2] cycloaddition”, Zhang, C.; Ji, W.; Liu, Y. A.; Song, C.*; Liao, X.* J. Nat. Prod. 2018, 81, 1065.
14. “Recent Progress in Methylation of (Hetero)Arenes”, Hu, L.; Liu, Y. A.; Liao, X.* Syn Lett. (SYNPACTS) 2018, 29, 375.
15. “Synthesis of Withasomnine and Pyrazole Derivatives via Intramolecular Dehydrogenative Cyclization, as well as Biological Evaluation of Withasomnine-based Scaffolds”, Xia, T.; Hu, Z.; Ji, W.; Zhang, S.; Shi, H.; Liu, C.; Pang, B.; Liu, G.; Liao, X.* Org. Chem. Fron. 2018, 5, 850.
16. “In situ generation of N-unsubstituted imines from alkyl azides and their applications for imine transfer via copper catalysis”, Hu, L.; Liu, Y. A.; Liao, X.* Sci. Adv. 2017, 3, e1700826 (Highlighted by Synform).
17. “Palladium-Catalyzed Cross-Coupling of Ethyl Bromodifluoroacetate with Aryl Bromides or Triflates and Cross-Coupling of Ethyl Bromofluoroacetate with Aryl Iodides”, Xia, T.; He, L.; Liu, Y. A.; Hartwig, J. F.*; Liao, X.* Org. Lett. 2017, 19, 2610.
18. “The Novel Toll-like Receptor 2 Agonist SUP3 Enhances Antigen Presentation and T cell Activation by Dendritic cells”, Guo, X.; Wu, N.; Shang, Y.; Liu, X.; Wu, T.; Zhou, Y.; Liu, X.; Huang, J.; Liao, X.*; Wu, L.* Front. Immunol. 2017, 8, 158/1-158/15.
19. “Transition-Metal-Free Synthesis of N-hydroxy Oxindoles via an Aza-Nazarov Type Reaction Involving Aza-Oxyallyl Cations”, Ji, W.; Liu, Y.; Liao, X.* Angew. Chem. Int. Ed. 2016, 55, 13286.
20. “Copper-Catalyzed 2, 2, 2-Trifluoroethylthiolation of Aryl Halides”, Chen, S.; Zhang, M.; Liao, X.*; Weng, Z.* J. Org. Chem. 2016, 81, 7993.
21. “Nickel-catalyzed Methylation of Aryl Halides with Deuterated Methyl Iodide”, Hu, L.; Liu, X.; Liao, X.* Angew. Chem. Int. Ed. 2016, 55, 9743.
22. “Access to the Pyrroloindoline Core via [3 + 2] Annulation as well as the Application in the Synthetic Approach to (±)-Minfiensine”, Ji, W.; Yao, L.; Liao, X.* Org. Lett. 2016, 18, 628.
23. “Enantioselective and Diastereoselective Azo-coupling/Iminium-Cyclization: A Unified Strategy for the Total Synthesis of (-)-Psychotriasine and (+)-Pestalazine B”, Li, Q.; Xia, T.; Yao, L.; Deng, H.*; Liao, X.* Chem. Sci. 2015, 6, 3599.
