Identification of a Novel ASCT2 (SLC1A5) Inhibitor by Dynamic Pharmacophore-Based Virtual Screening (In Submission)

Rui Chen, Jiali Huang, Yumeng Chen, Lian Qin, Xiaofei Li, Haoming Chen, Yuxiao Wang, Zhiyu Li, Ahmed R. Ali, Jinlei Bian

Highlights

• Discovery of novel scaffold ASCT2 lead compounds through virtual screening and activity assaying workflows

• Virtual screening workflows such as molecular dynamics simulations, molecular docking, and pharmacophore screening

• Based on the lead compounds, studied the drug-target conformational relationship, combined with the protein crystal structure, through molecular docking and MD simulation, designed and synthesized 31 novel inhibitors

• By screening for enzyme and cellular activity, obtained inhibitors with tumor cell inhibitory activity superior to positive drug V9302

Discovery of CLKs Inhibitors for the Treatment of Non-small Cell Lung Cancer Eur. J. Med. Chem. 2024, 280, 116952

Tianxing Hu, Hui Zhang, Rui Chen, Jiangli Huang, Mai Liu, Wenyi Zhou, Depeng Li, Zhiyu Li, Jinlei Bian (First author, co-authored by 3)

Highlights

• Design and synthesis of novel CLK2 inhibitors

• LBM22 has significant antiproliferative activity in H1299 cells

• LBM22 can dose-dependently inhibit SR protein phosphorylation

• LBM22 down-regulates the expression of Wnt-related proteins and anti-apoptotic proteins

• CLK2 inhibitors show promise for the treatment of NSCLC

DNA Framework-Engineered Chimeras Platform Enables Selectively Targeted Protein Degradation. Nat. Commun. 2023, 14 (1), 4510.

Li Zhou, Bin Yu, Mengqiu Gao, Rui Chen, Zhiyu Li, Yueqing Gu, Jinlei Bian, Yi Ma

Highlights

• This paper developed a novel covalent DNA framework-based PROTACs (DbTACs), which can be used for a variety of different ligands and targets

• The programmability of the DNA framework allows precise control of the spatial distance between the degradation target protein (POI) and the E3 ligase ligand

Discovery of Selective and Potent Macrocyclic CDK9 Inhibitors for the Treatment of Osimertinib-Resistant Non-Small-Cell Lung Cancer. J. Med. Chem. 2023, 66 (22), 15340–15361.

Tizhi Wu, Bin Yu, Yifan Xu, Zekun Du, Zhiming Zhang, Yuxiao Wang, Haoming Chen, Li′ao Zhang, Rui Chen, Feihai Ma, Weihong Gong, Sixian Yu, Zhixia Qiu, Hongxi Wu, Xi Xu, Jubo Wang, Zhiyu Li, Jinlei Bian

Highlights

• Developed a novel macrocyclic CDK9 inhibitor for ositinib-resistant non-small cell lung cancer (NSCLC)

• A series of CDK9 inhibitors were designed by macrocyclization strategy based on protein structure analysis

• The dominant compounds were highly kinase-selective and also exhibited significant antitumor activity against oxitinib-resistant strains

A Patent Review of Selective CDK9 Inhibitors in Treating Cancer. Expert Opin. Ther. Pat. 2023, 33 (4), 309–322.

Tizhi Wu, Xiaowei Wu, Yifan Xu, Rui Chen, Jubo Wang, Zhiyu Li, Jinlei Bian

Highlights

• This review focuses on the development of selective CDK9 inhibitors reported in patent publications during the period 2020-2022

• Selective targeting of CDK9 is considered an effective strategy for antitumor drug development

An Updated Patent Review of Glutaminase Inhibitors (2019-2022). Expert Opin. Ther. Pat. 2023, 33 (1), 17–28.

Danni Wang, Xiaohong Li, Guangyue Gong, Yulong Lu, Ziming Guo, Rui Chen, Huidan Huang, Zhiyu Li, Jinlei Bian

Highlights

• This review covers recent patents (2019-present) involving GLS1 inhibitors, which are mostly focused on their chemical structures, molecular mechanisms of action, pharmacokinetic properties, and potential clinical applications

• Selective targeting of CDK9 is considered an effective strategy for antitumor drug development

Overview of the Development of Selective Androgen Receptor Modulators (SARMs) as Pharmacological Treatment for Osteoporosis (1998-2021). Eur. J. Med. Chem. 2022, 230, 114-119.

Youquan Xie, Yucheng Tian, Yuming Zhang, Zhisheng Zhang, Rui Chen, Mian Li, Jiawei Tang, Jinlei Bian, Zhiyu Li, XiXu

Highlights

• Summary of chemical scaffolds and corresponding SAR of SARMs as pharmacological treatment for osteoporosis from 1998 to 2021.

• Insight into advances and possible mechanisms of the potential toxicity, side effects, the abuse, and future perspectives of SARMs.

2023-2024

Projects

• Participated in the ACC017 project to design and synthesize relevant long-acting prodrugs by protecting possible metabolic sites of the drugs, and performed bioactivity tests to discover integrase inhibitors with novel structures

• Participated in the ACC027 project to explore novel coat protease inhibitors through molecular docking and molecular dynamics simulation combined with rational drug design

2022-2023

Projects

• ASCT2 subject refinement and completion of molecular dynamics modeling of ASCT2-related proteins and compounds

• Completion of work related to the modification, design and synthesis of target compounds

• Writing and defending a thesis

2022-2023

Projects

• Discovery of novel CLK2 inhibitors based on structure‐based drug design

• Enhanced water solubility and formulation properties of the lead compound

• Improved antiproliferative activity against H1299 cells

• Co-first author, published in Eur. J. Med. Chem., under minor revision

2022-2023

Projects

• Help labs purchase and build high-performance computer hardware and build CADD workstations

• Completed molecular docking and molecular dynamics simulation calculations and mapping in several topics

2022-2023

Projects

• Supervise undergraduate experiments and assist in the advancement of LAT1 target projects involving undergraduate students

• Assist undergraduate students with review writing

2021-2022

Projects

• Participated in the process optimization process of the new JAK inhibitor, optimized some process parameters and improved the overall yield

• Improved recrystallization parameters for compound intermediates resulted in rapid synthesis of kilogram-sized products

2021-2022

Projects

• Learning the molecular docking process on your own, exploring the application of molecular docking in drug design, and outputting results using software such as Pymol

• Self-study kinetic simulation tutorials to master drug molecule interactions in proteins and guide drug design efforts

2021-2022

Projects

• Participated in the synthesis and design of warhead compounds for DbTACs and screened several linkage chains of different lengths

• Complete protein-DNA docking in DbTACs to generate and optimize images for experiments

2021-2022

Projects

• Participated in the design and synthesis of a series of DON prodrugs.

• Improved the original toxic effects of DON through the design of the prodrug, and improved the plasma stability and tolerability of DON