Jorge Fortanet

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.

Protein tyrosine phosphatase SHP2 is an oncoprotein associated with cancer as well as a potential immune modulator because of its role in the programmed cell death PD-L1/PD-1 pathway. In the preceding manuscript, we described the optimization of a fused, bicyclic screening hit for potency, selectivity, and physicochemical properties in order to further expand the chemical diversity of allosteric SHP2 inhibitors. In this manuscript, we describe the further expansion of our approach, morphing the fused, bicyclic system into a novel monocyclic pyrimidinone scaffold through our understanding of SAR and use of structure-based design. These studies led to the identification of SHP394 (1), an orally efficacious inhibitor of SHP2, with high lipophilic efficiency, improved potency, and enhanced pharmacokinetic properties. We also report other pyrimidinone analogues with favorable pharmacokinetic and potency profiles. Overall, this work improves upon our previously described allosteric inhibitors and exemplifies and extends the range of permissible chemical templates that inhibit SHP2 via the allosteric mechanism.

SHP2 is a nonreceptor protein tyrosine phosphatase within the mitogen-activated protein kinase (MAPK) pathway controlling cell growth, differentiation, and oncogenic transformation. SHP2 also participates in the programed cell death pathway (PD-1/PD-L1) governing immune surveillance. Small-molecule inhibition of SHP2 has been widely investigated, including in our previous reports describing SHP099 (2), which binds to a tunnel-like allosteric binding site. To broaden our approach to allosteric inhibition of SHP2, we conducted additional hit finding, evaluation, and structure-based scaffold morphing. These studies, reported here in the first of two papers, led to the identification of multiple 5,6-fused bicyclic scaffolds that bind to the same allosteric tunnel as 2. We demonstrate the structural diversity permitted by the tunnel pharmacophore and culminated in the identification of pyrazolopyrimidinones (e.g., SHP389, 1) that modulate MAPK signaling in vivo. These studies also served as the basis for further scaffold morphing and optimization, detailed in the following manuscript.

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to Optimization of Fused Bicyclic Allosteric SHP2 InhibitorsJeffrey T. BagdanoffJeffrey T. BagdanoffMore by Jeffrey T. Bagdanoff, Zhouliang ChenZhouliang ChenMore by Zhouliang Chen, Michael AckerMichael AckerMore by Michael Acker, Ying-Nan ChenYing-Nan ChenMore by Ying-Nan Chen, Homan ChanHoman ChanMore by Homan Chan, Michael DoreMichael DoreMore by Michael Dore, Brant FirestoneBrant FirestoneMore by Brant Firestone, Michelle FodorMichelle FodorMore by Michelle Fodor, Jorge FortanetJorge FortanetMore by Jorge Fortanet, Murphy HentemannMurphy HentemannMore by Murphy Hentemann, Mitsunori KatoMitsunori KatoMore by Mitsunori Kato, Robert KoenigRobert KoenigMore by Robert Koenig, Laura R. LaBonteLaura R. LaBonteMore by Laura R. LaBonte, Shumei LiuShumei LiuMore by Shumei Liu, Movarid MohseniMovarid MohseniMore by Movarid Mohseni, Rukundo NtagandaRukundo NtagandaMore by Rukundo Ntaganda, Patrick SarverPatrick SarverMore by Patrick Sarver, Michael D. ShultzMichael D. ShultzMore by Michael D. Shultzhttp://orcid.org/0000-0001-7920-955X, Troy SmithTroy SmithMore by Troy Smith, Martin SendzikMartin SendzikMore by Martin Sendzik, Travis StamsTravis StamsMore by Travis Stams, Stan SpenceStan SpenceMore by Stan Spence, Christopher TowlerChristopher TowlerMore by Christopher Towler, Hongyun WangHongyun WangMore by Hongyun Wang, Ping WangPing WangMore by Ping Wang, Sarah L. WilliamsSarah L. WilliamsMore by Sarah L. Williams, and Matthew J. LaMarche*Matthew J. LaMarcheMore by Matthew J. LaMarchehttp://orcid.org/0000-0002-6588-2302Cite this: J. Med. Chem. 2019, 62, 7, 3780Publication Date (Web):March 22, 2019Publication History Published online22 March 2019Published inissue 11 April 2019https://doi.org/10.1021/acs.jmedchem.9b00435Copyright © 2019 American Chemical SocietyRIGHTS & PERMISSIONSACS AuthorChoiceArticle Views1886Altmetric-Citations2LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (277 KB) Get e-Alerts Get e-Alerts

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to 6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 InhibitorsPatrick SarverPatrick SarverMore by Patrick Sarver, Michael AckerMichael AckerMore by Michael Acker, Jeffrey T. BagdanoffJeffrey T. BagdanoffMore by Jeffrey T. Bagdanoff, Zhouliang ChenZhouliang ChenMore by Zhouliang Chen, Ying-Nan ChenYing-Nan ChenMore by Ying-Nan Chen, Homan ChanHoman ChanMore by Homan Chan, Brant FirestoneBrant FirestoneMore by Brant Firestone, Michelle FodorMichelle FodorMore by Michelle Fodor, Jorge FortanetJorge FortanetMore by Jorge Fortanet, Huaixiang HaoHuaixiang HaoMore by Huaixiang Hao, Murphy HentemannMurphy HentemannMore by Murphy Hentemann, Andriana JoukAndriana JoukMore by Andriana Jouk, Mitsunori KatoMitsunori KatoMore by Mitsunori Kato, Robert KoenigRobert KoenigMore by Robert Koenig, Laura R. LaBonteLaura R. LaBonteMore by Laura R. LaBonte, Gang LiuGang LiuMore by Gang Liu, Shumei LiuShumei LiuMore by Shumei Liu, Chen LiuChen LiuMore by Chen Liu, Eric McNeillEric McNeillMore by Eric McNeill, Morvarid MohseniMorvarid MohseniMore by Morvarid Mohseni, Michael D. ShultzMichael D. ShultzMore by Michael D. Shultzhttp://orcid.org/0000-0001-7920-955X, Martin SendzikMartin SendzikMore by Martin Sendzik, Travis StamsTravis StamsMore by Travis Stams, Stan SpenceStan SpenceMore by Stan Spence, Victoriano TamezVictoriano TamezMore by Victoriano Tamez, Ritesh TichkuleRitesh TichkuleMore by Ritesh Tichkule, Christopher TowlerChristopher TowlerMore by Christopher Towler, Hongyun WangHongyun WangMore by Hongyun Wang, Ping WangPing WangMore by Ping Wang, Sarah L. WilliamsSarah L. WilliamsMore by Sarah L. Williams, Bing YuBing YuMore by Bing Yu, and Matthew J. LaMarche*Matthew J. LaMarcheMore by Matthew J. LaMarchehttp://orcid.org/0000-0002-6588-2302Cite this: J. Med. Chem. 2019, 62, 7, 3781Publication Date (Web):March 22, 2019Publication History Published online22 March 2019Published inissue 11 April 2019https://doi.org/10.1021/acs.jmedchem.9b00436Copyright © 2019 American Chemical SocietyRIGHTS & PERMISSIONSACS AuthorChoiceArticle Views1622Altmetric-Citations2LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (281 KB) Get e-Alerts Get e-Alerts