PMID- 36985458
OWN - NLM
STAT- MEDLINE
DCOM- 20230330
LR  - 20230331
IS  - 1420-3049 (Electronic)
IS  - 1420-3049 (Linking)
VI  - 28
IP  - 6
DP  - 2023 Mar 8
TI  - Synthesis and Biological Evaluation of 3-Amino-4,4-Dimethyl Lithocholic Acid 
      Derivatives as Novel, Selective, and Cellularly Active Allosteric SHP1 
      Activators.
LID - 10.3390/molecules28062488 [doi]
LID - 2488
AB  - Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1), a 
      non-receptor member of the protein tyrosine phosphatase (PTP) family, negatively 
      regulates several signaling pathways that are responsible for pathological cell 
      processes in cancers. In this study, we report a series of 3-amino-4,4-dimethyl 
      lithocholic acid derivatives as SHP1 activators. The most potent compounds, 
      5az-ba, showed low micromolar activating effects (EC(50): 1.54-2.10 muM) for SHP1, 
      with 7.63-8.79-fold maximum activation and significant selectivity over the 
      closest homologue Src homology 2 domain-containing protein tyrosine phosphatase 2 
      (SHP2) (>32-fold). 5az-ba showed potent anti-tumor effects with IC(50) values of 
      1.65-5.51 muM against leukemia and lung cancer cells. A new allosteric mechanism 
      of SHP1 activation, whereby small molecules bind to a central allosteric pocket 
      and stabilize the active conformation of SHP1, was proposed. The activation 
      mechanism was consistent with the structure-activity relationship (SAR) data. 
      This study demonstrates that 3-amino-4,4-dimethyl lithocholic acid derivatives 
      can be selective SHP1 activators with potent cellular efficacy.
FAU - Chen, Huiqing
AU  - Chen H
AD  - Shanghai Engineering Research Center of Molecular Therapeutics and New Drug 
      Development, School of Chemistry and Molecular Engineering, East China Normal 
      University, Shanghai 200062, China.
FAU - Liu, Zekun
AU  - Liu Z
AD  - Shanghai Engineering Research Center of Molecular Therapeutics and New Drug 
      Development, School of Chemistry and Molecular Engineering, East China Normal 
      University, Shanghai 200062, China.
FAU - Gao, Lixin
AU  - Gao L
AD  - National Center for Drug Screening, Shanghai Institute of Material Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
AD  - School of Pharmaceutical Science, Jiangnan University, Wuxi 214122, China.
FAU - Yu, Li-Fang
AU  - Yu LF
AUID- ORCID: 0000-0002-3250-6773
AD  - Shanghai Engineering Research Center of Molecular Therapeutics and New Drug 
      Development, School of Chemistry and Molecular Engineering, East China Normal 
      University, Shanghai 200062, China.
FAU - Zhou, Yubo
AU  - Zhou Y
AD  - National Center for Drug Screening, Shanghai Institute of Material Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
AD  - Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
FAU - Tang, Jie
AU  - Tang J
AD  - Shanghai Engineering Research Center of Molecular Therapeutics and New Drug 
      Development, School of Chemistry and Molecular Engineering, East China Normal 
      University, Shanghai 200062, China.
AD  - Shanghai Greenchem & Biotech Co., Ltd., Shanghai 200062, China.
FAU - Li, Jia
AU  - Li J
AD  - National Center for Drug Screening, Shanghai Institute of Material Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
AD  - Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
FAU - Yang, Fan
AU  - Yang F
AUID- ORCID: 0000-0002-0411-7391
AD  - Shanghai Engineering Research Center of Molecular Therapeutics and New Drug 
      Development, School of Chemistry and Molecular Engineering, East China Normal 
      University, Shanghai 200062, China.
LA  - eng
GR  - 115/National Development and Reform Commission/
PT  - Journal Article
DEP - 20230308
PL  - Switzerland
TA  - Molecules
JT  - Molecules (Basel, Switzerland)
JID - 100964009
RN  - EC 3.1.3.48 (PTPN6 protein, human)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 6)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatases)
SB  - IM
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism
MH  - *Signal Transduction
MH  - *Protein Tyrosine Phosphatases/metabolism
MH  - Phosphorylation
PMC - PMC10056611
OTO - NOTNLM
OT  - 3-amino-4,4-dimethyl lithocholic acid derivatives
OT  - SHP1
OT  - anti-tumor
OT  - selective activators
OT  - structure-activity relationships
COIS- The authors declare no conflict of interest.
EDAT- 2023/03/30 06:00
MHDA- 2023/03/30 06:11
PMCR- 2023/03/08
CRDT- 2023/03/29 01:55
PHST- 2023/02/14 00:00 [received]
PHST- 2023/03/02 00:00 [revised]
PHST- 2023/03/06 00:00 [accepted]
PHST- 2023/03/30 06:11 [medline]
PHST- 2023/03/29 01:55 [entrez]
PHST- 2023/03/30 06:00 [pubmed]
PHST- 2023/03/08 00:00 [pmc-release]
AID - molecules28062488 [pii]
AID - molecules-28-02488 [pii]
AID - 10.3390/molecules28062488 [doi]
PST - epublish
SO  - Molecules. 2023 Mar 8;28(6):2488. doi: 10.3390/molecules28062488.