8BIO

Crystal structure of human Ephrin type-A receptor 2 (EPHA2) Kinase domain in complex with MRAL5

Summary for 8BIO

• Entry DOI: 10.2210/pdb8bio/pdb
• Descriptor: Ephrin type-A receptor 2, 1,2-ETHANEDIOL, 8-(4-azanylbutyl)-6-[2-chloranyl-5-(trifluoromethyl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one, ... (4 entities in total)
• Functional Keywords: epha2, eck, typ i inhibitor, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 35695.56

Authors

Zhubi, R.,Rak, M.,Lucic, A.,Knapp, S.,Kraemer, A.,Structural Genomics Consortium (SGC) (deposition date: 2022-11-02, release date: 2022-11-23, Last modification date: 2024-01-31)

Primary citation

Rak, M.,Tesch, R.,Berger, L.M.,Shevchenko, E.,Raab, M.,Tjaden, A.,Zhubi, R.,Balourdas, D.I.,Joerger, A.C.,Poso, A.,Kramer, A.,Elson, L.,Lucic, A.,Kronenberger, T.,Hanke, T.,Strebhardt, K.,Sanhaji, M.,Knapp, S.
Shifting the selectivity of pyrido[2,3-d]pyrimidin-7(8H)-one inhibitors towards the salt-inducible kinase (SIK) subfamily.
Eur.J.Med.Chem., 254:115347-115347, 2023

PubMed Abstract: Salt-inducible kinases 1-3 (SIK1-3) are key regulators of the LKB1-AMPK pathway and play an important role in cellular homeostasis. Dysregulation of any of the three isoforms has been associated with tumorigenesis in liver, breast, and ovarian cancers. We have recently developed the dual pan-SIK/group I p21-activated kinase (PAK) chemical probe MRIA9. However, inhibition of p21-activated kinases has been associated with cardiotoxicity in vivo, which complicates the use of MRIA9 as a tool compound. Here, we present a structure-based approach involving the back-pocket and gatekeeper residues, for narrowing the selectivity of pyrido[2,3-d]pyrimidin-7(8H)-one-based inhibitors towards SIK kinases, eliminating PAK activity. Optimization was guided by high-resolution crystal structure analysis and computational methods, resulting in a pan-SIK inhibitor, MR22, which no longer exhibited activity on STE group kinases and displayed excellent selectivity in a representative kinase panel. MR22-dependent SIK inhibition led to centrosome dissociation and subsequent cell-cycle arrest in ovarian cancer cells, as observed with MRIA9, conclusively linking these phenotypic effects to SIK inhibition. Taken together, MR22 represents a valuable tool compound for studying SIK kinase function in cells.

PubMed: 37094449
DOI: 10.1016/j.ejmech.2023.115347

Experimental method

X-RAY DIFFRACTION (1.6 Å)