7B30

MST3 in complex with compound G-5555

7B30 の概要

• エントリーDOI: 10.2210/pdb7b30/pdb
• 分子名称: Serine/threonine-protein kinase 24, 8-[(trans-5-amino-1,3-dioxan-2-yl)methyl]-6-[2-chloro-4-(6-methylpyridin-2-yl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (3 entities in total)
• 機能のキーワード: kinase inhibitors, structure-based drug design, sik2 inhibitor, structural genomics consortium, sgc, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35052.61

構造登録者

Tesch, R.,Rak, M.,Joerger, A.C.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2020-11-28, 公開日: 2020-12-16, 最終更新日: 2024-01-31)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.1 Å)