1.Design of the First‐in‐Class, Highly Potent Irreversible Inhibitor Targeting the Menin‐MLL Protein–Protein Interaction. Using a powerful structure-based design approach, we have successfully obtained the first-in-class, highly potent and irreversible menin inhibitors. A representative compound M-525 binds to menin with an IC50 value of 3 nM. It specifically inhibits the proliferation of MV4; 11 and MOLM-13 cell lines bearing MLL fusion with IC50 = 2.7 nM and 15.4 nM, respectively, and displays about 500-fold less potent against HL-60 cell line lacking MLL fusion. Further optimization based on this series of compounds may give us new menin inhibitors with better drug-like properties, which may be used for the treatment of MLL leukemia.

2.Design and synthesis novel mutant-selective inhibitors targeting EGFR T790M. We have got two series of pyrimidine-based EGFR inhibitors, One of which is pyrimido-[4,5-d]pyrimidin-4(1H)-one based EGFR T790M inhibitors. These new inhibitors bind tightly with EGFRT790M and EGFRL858R/T790M and are over 100 times less potent with respect to wild type EGFR. The other series is C-5 substituted pyrido[2,3-d]pyrimidin-7-ones which have improved mutant selectivity and pharmacokinetic properties. One representative compound XTF-262 displays promising anticancer efficacy in a human NSCLC (H1975) xenograft nude mouse model testing. Kinase profiling investigations against a panel of 456 kinases reveal that XTF-262 displays excellent selectivity on EGFRT790M mutants at 100 nM, and the S(35) selectivity score of it is 0.01. The extraordinary selectivity of the compounds over wild-type EGFR and other kinases makes them attractive lead compounds for future drug development.

3.Design of small molecules targeting protein degradation. We have designed two series of compounds which can efficiently and selectively induce critical proteins (ALK or AR) degradation in cancer cells. Several of them have good drug properties and displayed promising anticancer efficacy in vivo.

Patents:
1.Ding, K.; Xu, T.; Chang, S.; Zhang, L.; Luo, J.; Xu, S.; Xiao. Y.; Tu, Z.; Tricyclic or Tetracyclic Pyrimidine Scaffold Based Compounds, their Preparation and Use in Therapy, Chinese patent application: ZL201210266329.3.(Grant)
2.Ding, K.; Xu, T.; Ding, F.; Zhang, L.; Lu, X.; Li. W.; Ding, J.; Geng, M., 7-oxopyridopyrimidine Compounds, their Preparation and Use in therapy, Chinese patent application : ZL201210480885.0 (Grant) PCT application number: CN2013/080758.
3.Ding, K.; Xu, S.; Xu, T.; Zhang, L.; Ding, F.; Tu, Z.; Lu, X.; Ding, J.; Geng, M., Heterocyclicpyrimidine derivatives, their Preparation and Use in therapy, Chinese patent application: ZL201310365460.X. (Grant)
4.Wang, S.; Aguilar, A.; Zheng, K.; Xu, S.; Xu, T.; Bernard, D.; Huang, L.，Piperidines as menin inhibitors，US patent application: WO2017192543A1.
5.Wang, S.; Aguilar, A.; Xu, S.; Bernard, D.; Huang, L.; Stuckey, J.; Xu, T.，Piperidines as covalent menin inhibitors, US patent application: WO2018183857A1.

1.Excellent Student Scholarship of Guangzhou Institutes of Biomedicine and Health
2.Excellent Student of Chinese Academy of Sciences
3.Paul Scholarship of Guangzhou Institutes of Biomedicine and Health

1.Xu, S.*; Aguilar, A.*; Xu, T.*; Zheng, K.*; Huang, L.*; Stuckey, J.; Chinnaswamy, K.; Bernard, D.; Fernández-Salas, E.; Liu, L., Wang, M.; McEachern, D.; Przybranowski, S.; Foster, C.; Wang, S., Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein–Protein Interaction, Angew Chem Int Edit. 2018, 57 (6), 1601-1605. (*co-first author)
2.Xu, T. *; Peng, T. *; Ren, X.*; Zhang, L.; Yu, L.; Luo, J.; Zhang, Z.; Tu, Z.; Tong, L.; Huang, Z.; Lu, X.; Geng, M.; Xie, H.; Ding, J.; Ding, K., C5-substituted pyrido [2, 3-d] pyrimidin-7-ones as highly specific kinase inhibitors targeting the clinical resistance-related EGFR T790M mutant, MedChemComm. 2015, 6(9), 1693-1697.
3.Xu, T. *; Zhang, L*.; Xu, S.; Yang, C.; Luo, J.; Ding, F.; Lu, X.; Liu, Y.; Tu, Z.; Li, L.; Pei, D.; Cai, Q.; Li, H.; Ren, X.; Wang, S.; Ding, K., Pyrimido[4,5-d]pyrimidin-4(1H)-one Derivatives as Selective Inhibitors of EGFR Threonine790 to Methionine790 (T790M) Mutants, Angew Chem Int Edit. 2013, 52(32),8387-8390.
4.Han, X.; Wang, C.; Qin, C.; Xiang, W.; Fernandez-Salas, E.; Yang, C.-Y.; Wang, M.; Zhao, L.; Xu, T.; Chinnaswamy, K.; Delproposto, J.; Stuckey, J.; Wang, S., Discovery of ARD-69 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor (AR) for the Treatment of Prostate Cancer. J Med Chem. 2019, 62 (2), 941-964 .
5.Yu, L.; Huang, M.; Xu, T.; Tong, L.; Yan, X.; Zhang, Z.; Xu, Y.; Yun, C.; Xie, H.; Ding, K.; Lu, X., A structure-guided optimization of pyrido [2, 3-d] pyrimidin-7-ones as selective inhibitors of EGFR L858R/T790M mutant with improved pharmacokinetic properties, Eur J Med Chem. 2017, 126, 1107-1117.
6.Xu, S.; Xu, T.; Zhang, L.; Zhang, Z.; Luo, J.; Liu, Y.; Lu, X.; Tu, Z.; Ren, X.; Ding, K., Design, Synthesis, and Biological Evaluation of 2-Oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl Derivatives as New Irreversible Epidermal Growth Factor Receptor Inhibitors with Improved Pharmacokinetic Properties, J Med Chem. 2013, 56(21), 8803-8813.