Citation: Lei Xu, Xuyang Mu, Minmin Liu, Zhijia Wang, Chao Shen, Qianwen Mu, Bo Feng, Yechun Xu, Tingjun Hou, Lixin Gao, Haini Jiang, Jia Li, Yubo Zhou, Wenlong Wang. Novel thieno[2,3-b]quinoline-procaine hybrid molecules: A new class of allosteric SHP-1 activators evolved from PTP1B inhibitors[J]. Chinese Chemical Letters, ;2023, 34(8): 108063. doi: 10.1016/j.cclet.2022.108063 shu

Novel thieno[2,3-b]quinoline-procaine hybrid molecules: A new class of allosteric SHP-1 activators evolved from PTP1B inhibitors

Lei Xu ^{a, b, c, 1} ,
Xuyang Mu ^{a, d, 1} ,
Minmin Liu ^{a, b, 1} ,
Zhijia Wang ^{a, b, 1} ,
Chao Shen ^e ,
Qianwen Mu ^b ,
Bo Feng ^b ,
Yechun Xu ^b ,
Tingjun Hou ^e ,
Lixin Gao ^{a, b} ,
Haini Jiang ^c ,
Jia Li ^{b, c, f, *,} ,
Yubo Zhou ^{b, c, *,} ,
Wenlong Wang ^{a, b, d, *,}

a.
School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China
b.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
c.
Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China
d.
School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, China
e.
Innovation Institute for Artificial Intelligence in Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
f.
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China

jli@simm.ac.cn

ybzhou@simm.ac.cn

wenlongwang@jiangnan.edu.cn

Received Date: 28 August 2022
Revised Date: 21 November 2022
Accepted Date: 12 December 2022
Available Online: 15 December 2022

Figures(4)

Small molecule activators could equally provide powerful tools as inhibitors do for interrogating cellular signal transduction. However, targeted protein activation is chemically challenging. Developing activators against Src homology region 2 domain-containing phosphatase-1 (SHP-1) to block STAT3 pathway represents a promising strategy for DLBCL therapy. Here we reported a new class of thieno[2,3-b]quinoline-procaine hybrid molecules as SHP-1 allosteric activators. The representative hybrid compound 3b displayed SHP-1 activating effect with EC₅₀ of 5.48 ± 0.28 µmol/L. Further investigations confirmed that 3b allosterically interacted with SHP-1, switched it from close to open conformation, blocked SHP-1/p-STAT3 pathway, induced apoptosis and inhibited ABC-DLBCL cell proliferation in vitro, and delayed tumor growth in the xenograft model of SU-DHL-2. Overall, this work offered a novel paradigm to develop SHP-1 allosteric activators through chemical space evolution of PTPs inhibitors, and firstly validated the therapeutic strategy that directly activating SHP-1 alone could be a potential therapy against ABC-DLBCL via blocking STAT3 pathway.
- Activator,
- PTPs,
- Inhibitor,
- Thieno[2,3-b]quinoline derivatives,
- Diffuse large B-cell lymphoma
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