PMID- 37836790
OWN - NLM
STAT- MEDLINE
DCOM- 20231023
LR  - 20240210
IS  - 1420-3049 (Electronic)
IS  - 1420-3049 (Linking)
VI  - 28
IP  - 19
DP  - 2023 Oct 6
TI  - Discovery of a SHP2 Degrader with In Vivo Anti-Tumor Activity.
LID - 10.3390/molecules28196947 [doi]
LID - 6947
AB  - Src homology 2 domain-containing phosphatase 2 (SHP2) is an attractive target for 
      cancer therapy due to its multifaceted roles in both tumor and immune cells. 
      Herein, we designed and synthesized a novel series of proteolysis targeting 
      chimeras (PROTACs) using a SHP2 allosteric inhibitor as warhead, with the goal of 
      achieving SHP2 degradation both inside the cell and in vivo. Among these 
      molecules, compound P9 induces efficient degradation of SHP2 (DC(50) = 35.2 +/- 1.5 
      nM) in a concentration- and time-dependent manner. Mechanistic investigation 
      illustrates that the P9-mediated SHP2 degradation requires the recruitment of the 
      E3 ligase and is ubiquitination- and proteasome-dependent. P9 shows improved 
      anti-tumor activity in a number of cancer cell lines over its parent allosteric 
      inhibitor. Importantly, administration of P9 leads to a nearly complete tumor 
      regression in a xenograft mouse model, as a result of robust SHP2 depletion and 
      suppression of phospho-ERK1/2 in the tumor. Hence, P9 represents the first SHP2 
      PROTAC molecule with excellent in vivo efficacy. It is anticipated that P9 could 
      serve not only as a new chemical tool to interrogate SHP2 biology but also as a 
      starting point for the development of novel therapeutics targeting SHP2.
FAU - Miao, Jinmin
AU  - Miao J
AUID- ORCID: 0000-0001-7471-0847
AD  - Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 
      West Lafayette, IN 47907, USA.
FAU - Bai, Yunpeng
AU  - Bai Y
AUID- ORCID: 0000-0002-5879-3555
AD  - Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 
      West Lafayette, IN 47907, USA.
FAU - Miao, Yiming
AU  - Miao Y
AD  - Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 
      West Lafayette, IN 47907, USA.
FAU - Qu, Zihan
AU  - Qu Z
AUID- ORCID: 0009-0004-8446-8459
AD  - Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
FAU - Dong, Jiajun
AU  - Dong J
AUID- ORCID: 0000-0002-6901-5070
AD  - Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 
      West Lafayette, IN 47907, USA.
FAU - Zhang, Ruo-Yu
AU  - Zhang RY
AD  - Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 
      West Lafayette, IN 47907, USA.
FAU - Aggarwal, Devesh
AU  - Aggarwal D
AD  - Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 
      West Lafayette, IN 47907, USA.
FAU - Jassim, Brenson A
AU  - Jassim BA
AD  - Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 
      West Lafayette, IN 47907, USA.
FAU - Nguyen, Quyen
AU  - Nguyen Q
AD  - Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
FAU - Zhang, Zhong-Yin
AU  - Zhang ZY
AUID- ORCID: 0000-0001-5527-7910
AD  - Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 
      West Lafayette, IN 47907, USA.
AD  - Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
AD  - Institute for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
AD  - Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA.
LA  - eng
GR  - R01 CA069202/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20231006
PL  - Switzerland
TA  - Molecules
JT  - Molecules (Basel, Switzerland)
JID - 100964009
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
SB  - IM
MH  - Humans
MH  - Animals
MH  - Mice
MH  - *Protein Tyrosine Phosphatase, Non-Receptor Type 11
MH  - *Neoplasms/drug therapy
MH  - Cell Line
MH  - Proteasome Endopeptidase Complex/metabolism
MH  - Ubiquitin-Protein Ligases/metabolism
MH  - Proteolysis
PMC - PMC10574094
OTO - NOTNLM
OT  - PROTAC
OT  - SHP2
OT  - anti-cancer agent
OT  - protein tyrosine phosphatase
OT  - target protein degradation
COIS- Z.-Y.Z. is an academic co-founder of Tyligand Bioscience. The other authors have 
      no competing interest to declare.
EDAT- 2023/10/14 10:48
MHDA- 2023/10/23 01:18
PMCR- 2023/10/06
CRDT- 2023/10/14 01:20
PHST- 2023/09/04 00:00 [received]
PHST- 2023/10/03 00:00 [revised]
PHST- 2023/10/04 00:00 [accepted]
PHST- 2023/10/23 01:18 [medline]
PHST- 2023/10/14 10:48 [pubmed]
PHST- 2023/10/14 01:20 [entrez]
PHST- 2023/10/06 00:00 [pmc-release]
AID - molecules28196947 [pii]
AID - molecules-28-06947 [pii]
AID - 10.3390/molecules28196947 [doi]
PST - epublish
SO  - Molecules. 2023 Oct 6;28(19):6947. doi: 10.3390/molecules28196947.