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

Garcia Fortanet, Jorge and Chen, Christine and Chen, Zhuoliang and Deng, Zhan and Firestone, Brant and Fekkes, Peter and Fodor, Michelle and Fortin, Pascal and Fridrich, Cary and Grunenfelder, Denise and Ho, Samuel and Kang, Zhao Bin and Karki, Rajesh and Kato, Mitsunori and Keen, Nicholas and Larrow, Jay and Lenoir, Francois and Liu, Gang and Liu, Shumei and Lombardo, Franco and Majumdar, Dyuti and Meyer, Matthew and Palermo, Mark and Perez, Lawrence and Pu, Minying and Ramsey, Timothy and Shultz, Michael and Stams, Travis and Towler, Christopher and Wang, Ping and Williams, Sarah and Zhang, Ji and Lamarche, Matthew and Sellers, William (2016) Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor. Journal of Medicinal Chemistry. ISSN 0022-26231520-4804

Abstract

SHP2 is a nonreceptor protein tyrosine phosphatase 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 programed cell death pathway (PD-1/PD-L1). As 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 labs, a novel allosteric mechanism of SHP2 inhibition was identified where the autoinhibited form of SHP2 is stabilized via small molecule binding. A high throughput screen was performed to identify progressible chemical matter and X-ray crystallography revealed the location of binding and in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize the hit pyrimidine scaffold for SHP2 inhibition and several new protein-ligand interactions were characterized. Further scaffold morphing of the hit chemical scaffold resulted in the identification of the pyrazine lead series. These studies culminated in the discovery of LMD099 (1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.

Item Type: Article
Date Deposited: 15 Jul 2016 00:45
Last Modified: 15 Jul 2016 00:45
URI: https://oak.novartis.com/id/eprint/27311

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