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”.
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.
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.
