From Pyrazolones to Azaindoles: Evolution of Active-Site SHP2 Inhibitors Based on Scaffold Hopping and Bioisosteric Replacement

  • J Med Chem. 2020 Dec 10;63(23):14780-14804. doi: 10.1021/acs.jmedchem.0c01265.
Yelena Mostinski  1 ,  Guus J J E Heynen  2 ,  Maria Pascual López-Alberca  1 ,  Jerome Paul  1 ,  Sandra Miksche  1 ,  Silke Radetzki  1 ,  David Schaller  3 ,  Elena Shanina  4 ,  Carola Seyffarth  1 ,  Yuliya Kolomeets  1 ,  Nandor Ziebart  1 ,  Judith de Schryver  1 ,  Sylvia Oestreich  1 ,  Martin Neuenschwander  1 ,  Yvette Roske  2 ,  Udo Heinemann  2 ,  Christoph Rademacher  4 ,  Andrea Volkamer  3 ,  Jens Peter von Kries  1 ,  Walter Birchmeier  2 ,  Marc Nazaré  1
Affiliations
  • 1. Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin, Germany.
  • 2. Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin, Germany.
  • 3. Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
  • 4. Max-Planck-Institut für Kolloid- und Grenzflächenforschung, Am Mühlenberg, 1, 14476 Potsdam, Germany.
PMID: 33210922 DOI: 10.1021/acs.jmedchem.0c01265
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 IC50 = 0.031 μM in an enzymatic assay and with an IC50 = 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.