2. Academic Validation
  3. Structure-Based Design of Selective Salt-Inducible Kinase Inhibitors

Structure-Based Design of Selective Salt-Inducible Kinase Inhibitors

  • J Med Chem. 2021 Jun 24;64(12):8142-8160. doi: 10.1021/acs.jmedchem.0c02144.
Roberta Tesch 1 2,  Marcel Rak 1 2,  Monika Raab 3,  Lena M Berger 1 2,  Thales Kronenberger 4 5,  Andreas C Joerger 1 2,  Benedict-Tilman Berger 1 2,  Ismahan Abdi 1 2,  Thomas Hanke 1 2,  Antti Poso 4 5,  Klaus Strebhardt 3,  Mourad Sanhaji 3,  Stefan Knapp 1 2 6
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Max-von-Laue-Str. 9, Frankfurt am Main 60438, Germany.
  • 2 Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Johann Wolfgang Goethe University, Max-von-Laue-Str. 15, Frankfurt am Main 60438, Germany.
  • 3 Department of Obstetrics and Gynaecology, School of Medicine, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany.
  • 4 Dept. of Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Str. 14, Tübingen 72076, Germany.
  • 5 School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, Kuopio 70210, Finland.
  • 6 German Translational Cancer Network (DKTK) and Frankfurt Cancer Institute (FCI), Frankfurt am Main 60438, Germany.
PMID: 34086472 DOI: 10.1021/acs.jmedchem.0c02144
Abstract

Salt-inducible kinases (SIKs) are key metabolic regulators. The imbalance in SIK function is associated with the development of diverse cancers, including breast, gastric, and ovarian cancers. Chemical tools to clarify the roles of SIK in different diseases are, however, sparse and are generally characterized by poor kinome-wide selectivity. Here, we have adapted the pyrido[2,3-d]pyrimidin-7-one-based p21-activated kinase (PAK) inhibitor G-5555 for the targeting of SIK, by exploiting differences in the back-pocket region of these kinases. Optimization was supported by high-resolution crystal structures of G-5555 bound to the known off-targets, MST3 and MST4, leading to a chemical probe, MRIA9, with dual SIK/PAK activity and excellent selectivity over other kinases. Furthermore, we show that MRIA9 sensitizes ovarian Cancer cells to treatment with the mitotic agent paclitaxel, confirming earlier data from genetic knockdown studies and suggesting a combination therapy with SIK inhibitors and paclitaxel for the treatment of paclitaxel-resistant ovarian Cancer.

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