PMID- 35408869
OWN - NLM
STAT- MEDLINE
DCOM- 20220413
LR  - 20220416
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 23
IP  - 7
DP  - 2022 Mar 23
TI  - Toward a Treatment of Cancer: Design and In Vitro/In Vivo Evaluation of Uncharged 
      Pyrazoline Derivatives as a Series of Novel SHP2 Inhibitors.
LID - 10.3390/ijms23073497 [doi]
LID - 3497
AB  - Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) is a 
      non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene, which 
      is involved in the RAS/MAPK cell signaling transduction process. SHP2 has been 
      shown to contribute to the progression of various cancers and is emerging as an 
      important target for anti-tumor drug research. However, past efforts to develop 
      SHP2 inhibitors into drugs have been unsuccessful owing to the positively charged 
      nature of the active site pocket tending to bind negatively charged groups that 
      are usually non-drug-like. Here, a series of uncharged pyrazoline derivatives 
      were designed and developed as new SHP2 inhibitors using a structure-based 
      strategy. Compound 4o, which exhibited the strongest SHP2 inhibitory activity, 
      bound directly to the catalytic domain of SHP2 in a competitive manner through 
      multiple hydrogen bonds. Compound 4o affected the RAS/MAPK signaling pathway by 
      inhibiting SHP2, and subsequently induced apoptosis and growth inhibition of 
      HCT116 cells in vitro and in vivo. Notably, the oral administration of compound 
      4o in large doses showed no obvious toxicity. In summary, our findings provide a 
      basis for the further development of compound 4o as a safe, effective and 
      anti-tumor SHP2 inhibitor.
FAU - Dai, Jiajia
AU  - Dai J
AD  - State Key Laboratory of Microbial Technology, Institute of Microbial Technology, 
      Shandong University, Qingdao 266200, China.
FAU - Zhang, Yiting
AU  - Zhang Y
AD  - State Key Laboratory of Microbial Technology, Institute of Microbial Technology, 
      Shandong University, Qingdao 266200, China.
FAU - Gao, Yanan
AU  - Gao Y
AD  - State Key Laboratory of Microbial Technology, Institute of Microbial Technology, 
      Shandong University, Qingdao 266200, China.
FAU - Bai, Xiaoyi
AU  - Bai X
AD  - State Key Laboratory of Microbial Technology, Institute of Microbial Technology, 
      Shandong University, Qingdao 266200, China.
FAU - Liu, Fang
AU  - Liu F
AD  - State Key Laboratory of Microbial Technology, Institute of Microbial Technology, 
      Shandong University, Qingdao 266200, China.
FAU - Li, Shuo
AU  - Li S
AD  - State Key Laboratory of Microbial Technology, Institute of Microbial Technology, 
      Shandong University, Qingdao 266200, China.
FAU - Yu, Yanyan
AU  - Yu Y
AD  - State Key Laboratory of Microbial Technology, Institute of Microbial Technology, 
      Shandong University, Qingdao 266200, China.
FAU - Hu, Wenpeng
AU  - Hu W
AD  - State Key Laboratory of Microbial Technology, Institute of Microbial Technology, 
      Shandong University, Qingdao 266200, China.
FAU - Shi, Ting
AU  - Shi T
AUID- ORCID: 0000-0003-1394-3000
AD  - College of Chemical and Biological Engineering, Shandong University of Science 
      and Technology, Qingdao 266590, China.
FAU - Shi, Dayong
AU  - Shi D
AD  - State Key Laboratory of Microbial Technology, Institute of Microbial Technology, 
      Shandong University, Qingdao 266200, China.
AD  - Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for 
      Marine Science and Technology, Qingdao 266071, China.
FAU - Li, Xiangqian
AU  - Li X
AUID- ORCID: 0000-0002-5807-5633
AD  - State Key Laboratory of Microbial Technology, Institute of Microbial Technology, 
      Shandong University, Qingdao 266200, China.
LA  - eng
GR  - 82003787/National Natural Science Foundation of China/
GR  - ZR2020QH364/Natural Science Foundation of Shandong Province/
GR  - 82104029/National Natural Science Foundation of China/
GR  - ZR2021LSW013/Joint fund of Shandong Natural Science Foundation/
GR  - 20-3-4-20-nsh/Qingdao Science and Technology Benefit People Demonstration Guide 
      Special Project/
GR  - 2020GN033/Fundamental Research Fund of Shandong University/
PT  - Journal Article
DEP - 20220323
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11)
SB  - IM
MH  - *Antineoplastic Agents/pharmacology/therapeutic use
MH  - Catalytic Domain
MH  - Enzyme Inhibitors/pharmacology
MH  - HCT116 Cells
MH  - Humans
MH  - *Neoplasms/drug therapy
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics
MH  - Signal Transduction
PMC - PMC8998978
OTO - NOTNLM
OT  - SHP2
OT  - anti-tumor
OT  - apoptosis
OT  - inhibitor
OT  - toxicity
COIS- The authors declare no conflict of interest.
EDAT- 2022/04/13 06:00
MHDA- 2022/04/14 06:00
PMCR- 2022/03/23
CRDT- 2022/04/12 01:11
PHST- 2022/02/26 00:00 [received]
PHST- 2022/03/19 00:00 [revised]
PHST- 2022/03/21 00:00 [accepted]
PHST- 2022/04/12 01:11 [entrez]
PHST- 2022/04/13 06:00 [pubmed]
PHST- 2022/04/14 06:00 [medline]
PHST- 2022/03/23 00:00 [pmc-release]
AID - ijms23073497 [pii]
AID - ijms-23-03497 [pii]
AID - 10.3390/ijms23073497 [doi]
PST - epublish
SO  - Int J Mol Sci. 2022 Mar 23;23(7):3497. doi: 10.3390/ijms23073497.