PMID- 34601294
OWN - NLM
STAT- MEDLINE
DCOM- 20220104
LR  - 20220104
IS  - 1090-2120 (Electronic)
IS  - 0045-2068 (Linking)
VI  - 116
DP  - 2021 Nov
TI  - Synthesis and biological evaluation of 2,5-diaryl-1,3,4-oxadiazole derivatives as 
      novel Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) 
      inhibitors.
PG  - 105384
LID - S0045-2068(21)00761-6 [pii]
LID - 10.1016/j.bioorg.2021.105384 [doi]
AB  - The Src homology-2 domain containing-protein tyrosine phosphatase-2 (SHP2) is a 
      convergent node for oncogenic cell-signaling cascades including the PD-L1/PD-1 
      pathway. As an oncoprotein as well as a potential immunomodulator, SHP2 has now 
      emerged as an attractive target for novel anti-cancer agents. Although 
      significant progress has been made in identifying chemotypes of SHP2 inhibitors, 
      these specific compounds might not be clinically useful to inhibit frequently 
      encountered mutated SHP2 variants. Consequently, it is highly desirable to 
      develop chemically different SHP2 inhibitors sensitive to SHP2 mutants. This work 
      developed a new type of SHP2 inhibitors with 2,5-diaryl-1,3,4-oxadiazole 
      scaffold. The representative compound 6l exhibited SHP2 inhibitory activity with 
      IC(50) of 2.73 +/- 0.20 microM, showed about 1.56-fold, 5.26-fold, and 7.36-fold 
      selectivity for SHP2 over SHP1, PTP1B and TCPTP respectively. Further 
      investigations confirmed that 6l behaved as mixed-type inhibitor sensitive to 
      leukemia cell TF-1 and inhibited SHP2 mediated cell signaling and proliferation. 
      Molecular dynamics simulation provided more detailed information on the binding 
      modes of compounds and SHP2 protein. These preliminary results could provide a 
      possible opportunity for the development of novel SHP2 inhibitors sensitive to 
      SHP2 mutants with optimal potency and improved pharmacological properties.
CI  - Copyright (c) 2021 Elsevier Inc. All rights reserved.
FAU - Meng, Xiang-Dong
AU  - Meng XD
AD  - School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China.
FAU - Gao, Li-Xin
AU  - Gao LX
AD  - School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China; State 
      key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese 
      Academy of Sciences, Shanghai 201203, China.
FAU - Wang, Zhi-Jia
AU  - Wang ZJ
AD  - School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China.
FAU - Feng, Bo
AU  - Feng B
AD  - State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China; Zhongshan Institute for Drug 
      Discovery, Institutes of Drug Discovery and Development, Chinese Academy of 
      Sciences, Zhongshan 528400, China.
FAU - Zhang, Chun
AU  - Zhang C
AD  - School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China; 
      School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, 
      China.
FAU - Satheeshkumar, Rajendran
AU  - Satheeshkumar R
AD  - Department of Organic Chemistry, Faculty of Chemistry and Pharmacy, Pontifical 
      Catholic University of Chile, Santiago 702843, Chile.
FAU - Li, Jia
AU  - Li J
AD  - State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
FAU - Zhu, Yun-Long
AU  - Zhu YL
AD  - The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical 
      University, Wuxi 214002, China. Electronic address: sequoia113847@163.com.
FAU - Zhou, Yu-Bo
AU  - Zhou YB
AD  - State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China; Zhongshan Institute for Drug 
      Discovery, Institutes of Drug Discovery and Development, Chinese Academy of 
      Sciences, Zhongshan 528400, China. Electronic address: ybzhou@simm.ac.cn.
FAU - Wang, Wen-Long
AU  - Wang WL
AD  - School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China. 
      Electronic address: wwenlong2011@163.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210923
PL  - United States
TA  - Bioorg Chem
JT  - Bioorganic chemistry
JID - 1303703
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Oxadiazoles)
RN  - 20O2F20OUR (1,3,4-oxadiazole)
RN  - EC 3.1.3.48 (PTPN11 protein, human)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11)
SB  - IM
MH  - Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Drug Screening Assays, Antitumor
MH  - Enzyme Inhibitors/chemical synthesis/chemistry/*pharmacology
MH  - Humans
MH  - Molecular Dynamics Simulation
MH  - Molecular Structure
MH  - Oxadiazoles/chemical synthesis/chemistry/*pharmacology
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 11/*antagonists & 
      inhibitors/metabolism
MH  - Structure-Activity Relationship
OTO - NOTNLM
OT  - 2,5-diphenyl-1,3,4-oxadiazole derivatives
OT  - Inhibitors
OT  - SHP2
OT  - Structure-activity relationships (SAR)
EDAT- 2021/10/04 06:00
MHDA- 2022/01/05 06:00
CRDT- 2021/10/03 20:50
PHST- 2021/06/02 00:00 [received]
PHST- 2021/08/16 00:00 [revised]
PHST- 2021/09/20 00:00 [accepted]
PHST- 2021/10/04 06:00 [pubmed]
PHST- 2022/01/05 06:00 [medline]
PHST- 2021/10/03 20:50 [entrez]
AID - S0045-2068(21)00761-6 [pii]
AID - 10.1016/j.bioorg.2021.105384 [doi]
PST - ppublish
SO  - Bioorg Chem. 2021 Nov;116:105384. doi: 10.1016/j.bioorg.2021.105384. Epub 2021 
      Sep 23.