MRIA9
目录号 : GC62657MRIA9 是 ATP 竞争性的、pan-SIK 和 PAK2/3 抑制剂,其对 SIK1、SIK2 和 SIK3 的 IC50 值分别为 516 nM, 180 nM 和 127 nM。
Cas No.:2750707-05-0
Sample solution is provided at 25 µL, 10mM.
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MRIA9 is an ATP-competitive, pan Salt-Inducible kinase (SIK) and PAK2/3 inhibitor, with IC50 values of 516 nM, 180 nM and 127 nM for SIK1, SIK2 and SIK3, respectively[1].
MRIA9 (5 μM) MRIA9 sensitizes SKOV3 cells to paclitaxel treatment through inducing pronounced apoptosis[1].MRIA9 (5 μM) with paclitaxel (2 nM) significantly enhances cell death in HeLa cells[1].MRIA9 strongly impedes centrosome function, causes mitotic spindle mispositioning in ovarian cancer cell lines, prevents the centrosome disjunction during the late G2 phase, and sensitized ovarian cancer cells and patient derived 3D-spheroids to paclitaxel treatment[2].
MRIA9 shows high oral bioavailability (F = 75-80%)[1].
[1]. Roberta Tesch, et al. Structure-Based Design of Selective Salt-Inducible Kinase Inhibitors. J Med Chem. 2021 Jun 24;64(12):8142-8160.
[2]. Monika Raab, et al. The Small-Molecule Inhibitor MRIA9 Reveals Novel Insights into the Cell Cycle Roles of SIK2 in Ovarian Cancer Cells. Cancers 2021, 13(15), 3658.
Cas No. | 2750707-05-0 | SDF | |
分子式 | C24H22ClFN6O3 | 分子量 | 496.92 |
溶解度 | 储存条件 | Store at -20°C | |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.0124 mL | 10.062 mL | 20.124 mL |
5 mM | 0.4025 mL | 2.0124 mL | 4.0248 mL |
10 mM | 0.2012 mL | 1.0062 mL | 2.0124 mL |
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The Small-Molecule Inhibitor MRIA9 Reveals Novel Insights into the Cell Cycle Roles of SIK2 in Ovarian Cancer Cells
Cancers (Basel) 2021 Jul 21;13(15):3658.PMID:34359562DOI:10.3390/cancers13153658.
The activity of the Salt inducible kinase 2 (SIK2), a member of the AMP-activated protein kinase (AMPK)-related kinase family, has been linked to several biological processes that maintain cellular and energetic homeostasis. SIK2 is overexpressed in several cancers, including ovarian cancer, where it promotes the proliferation of metastases. Furthermore, as a centrosome kinase, SIK2 has been shown to regulate the G2/M transition, and its depletion sensitizes ovarian cancer to paclitaxel-based chemotherapy. Here, we report the consequences of SIK2 inhibition on mitosis and synergies with paclitaxel in ovarian cancer using a novel and selective inhibitor, MRIA9. We show that MRIA9-induced inhibition of SIK2 blocks the centrosome disjunction, impairs the centrosome alignment, and causes spindle mispositioning during mitosis. Furthermore, the inhibition of SIK2 using MRIA9 increases chromosomal instability, revealing the role of SIK2 in maintaining genomic stability. Finally, MRIA9 treatment enhances the sensitivity to paclitaxel in 3D-spheroids derived from ovarian cancer cell lines and ovarian cancer patients. Our study suggests selective targeting of SIK2 in ovarian cancer as a therapeutic strategy for overcoming paclitaxel resistance.
Structure-Based Design of Selective Salt-Inducible Kinase Inhibitors
J Med Chem 2021 Jun 24;64(12):8142-8160.PMID:34086472DOI:10.1021/acs.jmedchem.0c02144.
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.