7B34

MST3 in complex with compound MRIA12

Summary for 7B34

• Entry DOI: 10.2210/pdb7b34/pdb
• Descriptor: Serine/threonine-protein kinase 24, 1,2-ETHANEDIOL, 8-[(5-azanyl-1,3-dioxan-2-yl)methyl]-6-[2-chloranyl-4-(3-fluoranyl-6-methyl-pyridin-2-yl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one, ... (4 entities in total)
• Functional Keywords: kinase inhibitors, structure-based drug design, sik2 inhibitor, structural genomics consortium, sgc, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 35505.07

Authors

Tesch, R.,Rak, M.,Joerger, A.C.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2020-11-28, release date: 2020-12-16, Last modification date: 2024-01-31)

Primary citation

Tesch, R.,Rak, M.,Raab, M.,Berger, L.M.,Kronenberger, T.,Joerger, A.C.,Berger, B.T.,Abdi, I.,Hanke, T.,Poso, A.,Strebhardt, K.,Sanhaji, M.,Knapp, S.
Structure-Based Design of Selective Salt-Inducible Kinase Inhibitors.
J.Med.Chem., 64:8142-8160, 2021

PubMed 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-]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.

PubMed: 34086472
DOI: 10.1021/acs.jmedchem.0c02144

Experimental method

X-RAY DIFFRACTION (2.1 Å)