From pyrazolones to azaindoles: evolution of active-site SHP2 inhibitors based on scaffold hopping and bioisosteric replacement

Item Type:	Article
Title:	From pyrazolones to azaindoles: evolution of active-site SHP2 inhibitors based on scaffold hopping and bioisosteric replacement
Creators Name:	Mostinski, Y. and Heynen, G.J.J.E. and López-Alberca, M.P. and Paul, J. and Miksche, S. and Radetzki, S. and Schaller, D. and Shanina, E. and Seyffarth, C. and Kolomeets, Y. and Ziebart, N. and de Schryver, J. and Oestreich, S. and Neuenschwander, M. and Roske, Y. and Heinemann, U. and Rademacher, C. and Volkamer, A. and von Kries, J.P. and Birchmeier, W. and Nazaré, M.
Abstract:	The tyrosine phosphatase SHP2 controls the activity of pivotal signaling pathways, including MAPK, JAK-STAT, and PI3K-Akt. Aberrant SHP2 activity leads to uncontrolled cell proliferation, tumorigenesis, and metastasis. SHP2 signaling was recently linked to drug resistance against cancer medications such as MEK and BRAF inhibitors. In this work, we present the development of a novel class of azaindole SHP2 inhibitors. We applied scaffold hopping and bioisosteric replacement concepts to eliminate unwanted structural motifs and to improve the inhibitor characteristics of the previously reported pyrazolone SHP2 inhibitors. The most potent azaindole 45 inhibits SHP2 with an IC(50) = 0.031 μM in an enzymatic assay and with an IC(50) = 2.6 μM in human pancreas cells (HPAF-II). Evaluation in a series of cellular assays for metastasis and drug resistance demonstrated efficient SHP2 blockade. Finally, 45 inhibited proliferation of two cancer cell lines that are resistant to cancer drugs and diminished ERK signaling.
Keywords:	Antineoplastic Agents, Antitumor Drug Screening Assays, Catalytic Domain, Cell Proliferation, Enzyme Inhibitors, Indoles, MAP Kinase Signaling System, Molecular Docking Simulation, Molecular Dynamics Simulation, Molecular Structure, Non-Receptor Type 11 Protein Tyrosine Phosphatase, Protein Binding, Pyrazolones, Structure-Activity Relationship, Tumor Cell Line
Source:	Journal of Medicinal Chemistry
ISSN:	0022-2623
Publisher:	American Chemical Society
Volume:	63
Number:	23
Page Range:	14780-14804
Date:	10 December 2020
Official Publication:	https://doi.org/10.1021/acs.jmedchem.0c01265
PubMed:	View item in PubMed

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