师资队伍 | 廖学斌, PhD
廖学斌
研究员，博士生导师
1995年毕业于北京大学化学与分子工程沙巴体育，1998-2004年期间在威斯康星大学密尔沃基分校（University of Wisconsin-Milwaukee）获得有机化学博士学位；2005-2008年期间随世界著名化学家 John F. Hartwig先后在耶鲁大学以及伊利诺伊大学香槟分校从事博士后研究；2009年至2012年在诺华功能基因组研究院（GNF）以高级研究员(PI)的身份开展药学研究。2012年9月正式加入沙巴体育投注官网药学系，任教授、博士导师。廖学斌博士于2013-2015年获得了“Tsinghua-Janssen Investigator”awards，2018年获“Roche Chinese Investigator Award”， 2020年获“The Thieme Chemistry Journals Award”。
研究方向
(1) 基于MAP4Ks激酶家族的免疫调节机制以及蛋白结构，研发小分子抑制剂以及对应的蛋白水解靶向嵌合体(Proteolysis Targeting Chimeras, PROTACs);
(2) 究表观调控对肿瘤和免疫细胞的影响,尤其研究去甲基化酶KDM5A对免疫治疗的影响;
(3)基于先天免疫系统研发针对癌症和自身性免疫病的小分子调节剂。一部分工作包括发展作用于各种TLRs的新型小分子配体工具库，然后利用工具小分子研究Toll样受体对先天免疫系统的各种调控机制以及如何影响获得性免疫系统；
(4) 以天然产物为导向的全合成及方法学研究。
(2) 究表观调控对肿瘤和免疫细胞的影响,尤其研究去甲基化酶KDM5A对免疫治疗的影响;
(3)基于先天免疫系统研发针对癌症和自身性免疫病的小分子调节剂。一部分工作包括发展作用于各种TLRs的新型小分子配体工具库，然后利用工具小分子研究Toll样受体对先天免疫系统的各种调控机制以及如何影响获得性免疫系统；
(4) 以天然产物为导向的全合成及方法学研究。
科学贡献
廖学斌实验室利用药物化学、各种筛选技术和结构生物学等手段理性设计工具小分子化合物研究先天免疫系统。例如：利用蛋白结构信息及新的筛选体系，课题组发现了新的TLR7和8的小分子激动剂以及TLR7小分子拮抗剂；并利用新的TLR7小分子激动剂开展了与PD-1抗体的癌症免疫组合治疗，不仅验证了“协同机制”，还发现了与PD-1抗体治疗效果密切相关的基因；另外，课题组基于新的蛋白结构信息，理性设计了造血祖蛋白激酶的小分子抑制剂，此抑制剂在癌症免疫治疗中极具前景；课题组还利用KMO的相关结构开展了小分子抑制剂的研究，这类小分子抑制剂将可能被用于对老年痴呆症和急性胰腺炎的治疗。
2.发现了组蛋白去甲基化酶KDM5A与PD-1抗体治疗的协同机制，此项研究不仅找到了一种可以预测PD-1抗体治疗效果的潜在生物标记物，还揭示了一种新的免疫组合疗法，这种组合疗法将大大提高免疫检验点阻断疗法的效果。
研究成果
1.HPK1是通过NFκB-Blimp1信号通路调控T细胞功能的关键激酶，MAP4K1KO CAR-T 细胞疗法，以及HPK1小分子抑制剂和相应PROTACs的研发都证明了HPK1是一个有前景的可成药靶点。另外，我们目前设计了全新的造血激酶-1（HPK1）的抑制剂，各种毒理、药理及CMC的研究已迅速开展。另外，对于HPK1基因编辑的CAR-T细胞治疗，已经在西京医院开展了探索性临床（NCT04037566）。这项探索临床已经验证了HPK1基因编辑的安全性，并已经初步验证了有效性，这项研究将拓展临床的适用性。
3. 除TLR7激动剂咪喹莫特被批准用于治疗尖锐湿疣外，其它的TLR7、8激动剂在临床上还未取得成功，主要原因是现有激动剂的治疗效果不显著或靶点本身激活带来了免疫相关不良反应（irAEs）。我们设计了一系列基于吡啶[3,2-d]嘧啶的具有强激动活性的TLR7/8双激动剂，作为单药或与PD-1/PD-L1阻断剂联合用药在肿瘤免疫治疗中具显著的潜力。
荣誉和奖项
沙巴体育投注官网-杨森研究员（Janssen-Tsinghua Investigator）（2013-2015）
Roche Chinese Investigator Award（2018）
The Thieme Chemistry Journals Award （2020）
代表性论文
Roche Chinese Investigator Award（2018）
The Thieme Chemistry Journals Award （2020）
代表性论文
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.
