title: Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor.
abstract: 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.
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Jorge
authors.initials: J
authors.lastname: Garcia Fortanet
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Christine Hiu-Tung
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Ying-Nan P
authors.initials: YN
authors.lastname: Chen
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Zhouliang
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Deng
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Brant
authors.initials: B
authors.lastname: Firestone
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Fekkes
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Michelle
authors.initials: M
authors.lastname: Fodor
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Pascal D
authors.initials: PD
authors.lastname: Fortin
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Cary
authors.initials: C
authors.lastname: Fridrich
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Denise
authors.initials: D
authors.lastname: Grunenfelder
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Samuel
authors.initials: S
authors.lastname: Ho
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Zhao B
authors.initials: ZB
authors.lastname: Kang
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Karki
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Kato
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Nick
authors.initials: N
authors.lastname: Keen
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Laura R
authors.initials: LR
authors.lastname: LaBonte
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Jay
authors.initials: J
authors.lastname: Larrow
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Francois
authors.initials: F
authors.lastname: Lenoir
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Shumei
authors.initials: S
authors.lastname: Liu
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Franco
authors.initials: F
authors.lastname: Lombardo
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Dyuti
authors.initials: D
authors.lastname: Majumdar
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Meyer
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Palermo
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Perez
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Minying
authors.initials: M
authors.lastname: Pu
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: Ramsey
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Shultz
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Travis
authors.initials: T
authors.lastname: Stams
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Towler
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Williams
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Ji-Hu
authors.initials: JH
authors.lastname: Zhang
authors.affiliation: Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: LaMarche
mesh_terms: D000284:Administration, Oral; D000494:Allosteric Regulation; D000495:Allosteric Site; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D005260:Female; D064593:Heterografts; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011487:Protein Conformation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D011719:Pyrazines; D011743:Pyrimidines; C000609471:SHP099; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11