PMID- 32437146
OWN - NLM
STAT- MEDLINE
DCOM- 20201207
LR  - 20201228
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 63
IP  - 14
DP  - 2020 Jul 23
TI  - Discovery of SHP2-D26 as a First, Potent, and Effective PROTAC Degrader of SHP2 
      Protein.
PG  - 7510-7528
LID - 10.1021/acs.jmedchem.0c00471 [doi]
AB  - Src homology 2 domain-containing phosphatase 2 (SHP2) is an attractive 
      therapeutic target for human cancers and other human diseases. Herein, we report 
      our discovery of potent small-molecule SHP2 degraders whose design is based upon 
      the proteolysis-targeting chimera (PROTAC) concept. This work has led to the 
      discovery of potent and effective SHP2 degraders, exemplified by SHP2-D26. 
      SHP2-D26 achieves DC(50) values of 6.0 and 2.6 nM in esophageal cancer KYSE520 
      and acute myeloid leukemia MV4;11 cells, respectively, and is capable of reducing 
      SHP2 protein levels by >95% in cancer cells. SHP2-D26 is >30-times more potent in 
      inhibition of phosphorylation of extracellular signal-regulated kinase (ERK) and 
      of cell growth than SHP099, a potent SHP2 inhibitor, in KYSE520 and MV4;11 cancer 
      cell lines. This study demonstrates that induced SHP2 degradation is a very 
      effective approach to inhibit the function of SHP2. Further optimization of these 
      SHP2 degraders may lead to the development of a new class of therapies for 
      cancers and other human diseases.
FAU - Wang, Mingliang
AU  - Wang M
FAU - Lu, Jianfeng
AU  - Lu J
FAU - Wang, Mi
AU  - Wang M
FAU - Yang, Chao-Yie
AU  - Yang CY
AUID- ORCID: 0000-0002-5445-0109
FAU - Wang, Shaomeng
AU  - Wang S
AUID- ORCID: 0000-0002-8782-6950
LA  - eng
GR  - P30 CA046592/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200521
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Cullin Proteins)
RN  - 0 (Dipeptides)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Ligands)
RN  - 0 (Piperidines)
RN  - 0 (Pyrazines)
RN  - 0 (Pyrimidines)
RN  - 0 (Pyrrolidines)
RN  - 0 (SHP099)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11)
SB  - IM
EIN - J Med Chem. 2021 Jan 14;64(1):906-908. PMID: 33356218
MH  - Antineoplastic Agents/chemical synthesis/pharmacology
MH  - Cell Line, Tumor
MH  - Cullin Proteins/metabolism
MH  - Dipeptides/chemical synthesis/*pharmacology
MH  - Drug Design
MH  - Drug Screening Assays, Antitumor
MH  - Enzyme Inhibitors/chemical synthesis/*pharmacology
MH  - Humans
MH  - Ligands
MH  - Piperidines/pharmacology
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 11/*antagonists & 
      inhibitors/metabolism
MH  - Proteolysis
MH  - Pyrazines/chemical synthesis/*pharmacology
MH  - Pyrimidines/pharmacology
MH  - Pyrrolidines/chemical synthesis/*pharmacology
EDAT- 2020/05/22 06:00
MHDA- 2020/12/15 06:00
CRDT- 2020/05/22 06:00
PHST- 2020/05/22 06:00 [pubmed]
PHST- 2020/12/15 06:00 [medline]
PHST- 2020/05/22 06:00 [entrez]
AID - 10.1021/acs.jmedchem.0c00471 [doi]
PST - ppublish
SO  - J Med Chem. 2020 Jul 23;63(14):7510-7528. doi: 10.1021/acs.jmedchem.0c00471. Epub 
      2020 May 21.