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Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor

Garcia Fortanet, Jorge ; Chen, Christine Hiu-Tung ; Chen, Ying-Nan P ; Chen, Zhouliang ; Deng, Zhan ; Firestone, Brant ; Fekkes, Peter ; Fodor, Michelle ; Fortin, Pascal D ; Fridrich, Cary ; Grunenfelder, Denise ; Ho, Samuel ; Kang, Zhao B ; Karki, Rajesh ; Kato, Mitsunori ; Keen, Nick ; LaBonte, Laura R ; Larrow, Jay ; Lenoir, Francois ; Liu, Gang ; Liu, Shumei ; Lombardo, Franco ; Majumdar, Dyuti ; Meyer, Matthew J ; Palermo, Mark ; Perez, Lawrence ; Pu, Minying ; Ramsey, Timothy ; Sellers, William R ; Shultz, Michael D ; Stams, Travis ; Towler, Christopher ; Wang, Ping ; Williams, Sarah L ; Zhang, Ji-Hu ; LaMarche, Matthew J

Journal of medicinal chemistry, 2016-09, Vol.59 (17), p.7773-7782 [Periódico revisado por pares]

United States: American Chemical Society

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Título:
Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor
Autor: Garcia Fortanet, Jorge ; Chen, Christine Hiu-Tung ; Chen, Ying-Nan P ; Chen, Zhouliang ; Deng, Zhan ; Firestone, Brant ; Fekkes, Peter ; Fodor, Michelle ; Fortin, Pascal D ; Fridrich, Cary ; Grunenfelder, Denise ; Ho, Samuel ; Kang, Zhao B ; Karki, Rajesh ; Kato, Mitsunori ; Keen, Nick ; LaBonte, Laura R ; Larrow, Jay ; Lenoir, Francois ; Liu, Gang ; Liu, Shumei ; Lombardo, Franco ; Majumdar, Dyuti ; Meyer, Matthew J ; Palermo, Mark ; Perez, Lawrence ; Pu, Minying ; Ramsey, Timothy ; Sellers, William R ; Shultz, Michael D ; Stams, Travis ; Towler, Christopher ; Wang, Ping ; Williams, Sarah L ; Zhang, Ji-Hu ; LaMarche, Matthew J
Assuntos: 60 APPLIED LIFE SCIENCES ; Administration, Oral ; Allosteric Regulation ; Allosteric Site ; amines ; Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - pharmacology ; Cell Line, Tumor ; conformation ; Crystallography, X-Ray ; Drug Design ; Female ; Heterografts ; High-Throughput Screening Assays ; Humans ; inhibition ; inhibitors ; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY ; Male ; Mice, Inbred C57BL ; Mice, Nude ; Models, Molecular ; Neoplasm Transplantation ; peptides and proteins ; Piperidines - chemical synthesis ; Piperidines - chemistry ; Piperidines - pharmacokinetics ; Piperidines - pharmacology ; Protein Conformation ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - antagonists & inhibitors ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - chemistry ; Pyrazines - chemical synthesis ; Pyrazines - chemistry ; Pyrazines - pharmacokinetics ; Pyrazines - pharmacology ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacokinetics ; Pyrimidines - pharmacology ; Structure-Activity Relationship
É parte de: Journal of medicinal chemistry, 2016-09, Vol.59 (17), p.7773-7782
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
AC02-06CH11357
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Descrição: SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein–ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.
Editor: United States: American Chemical Society
Idioma: Inglês

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Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor

United States: American Chemical Society

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