BRD0705
目录号 : GC39181BRD0705 is a potent, paralog selective and orally active inhibitor of GSK3α (Glycogen synthase kinase 3α) with IC50 of 66 nM and Kd of 4.8 μM. BRD0705 also inhibits GSK3β with IC50 of 515 nM. BRD0705 can be used for acute myeloid leukemia (AML).
Cas No.:2056261-41-5
Sample solution is provided at 25 µL, 10mM.
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BRD0705 is a potent, paralog selective and orally active inhibitor of GSK3α (Glycogen synthase kinase 3α) with IC50 of 66 nM and Kd of 4.8 μM. BRD0705 also inhibits GSK3β with IC50 of 515 nM. BRD0705 can be used for acute myeloid leukemia (AML).
BRD0705 inhibits kinase function and does not stabilize β-catenin, mitigating potential neoplastic concerns. BRD0705 induces myeloid differentiation and impairs colony formation in AML cells while no effect is observed on normal hematopoietic cells.[1]
BRD0705 impairs leukemia initiation and prolongs survival in AML mouse models.[1]
[1] Florence F Wagner, et al. Sci Transl Med. 2018 Mar 7;10(431):eaam8460.
Cas No. | 2056261-41-5 | SDF | |
Canonical SMILES | O=C1C2=C(N=C3C([C@]2(CC)C4=CC=CC=C4)=CNN3)CC(C)(C)C1 | ||
分子式 | C20H23N3O | 分子量 | 321.42 |
溶解度 | DMSO: 300 mg/mL (933.36 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 3.1112 mL | 15.556 mL | 31.1119 mL |
5 mM | 0.6222 mL | 3.1112 mL | 6.2224 mL |
10 mM | 0.3111 mL | 1.5556 mL | 3.1112 mL |
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2.
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Roles of glycogen synthase kinase 3 alpha and calcineurin in regulating the ability of sperm to fertilize eggs
FASEB J 2020 Jan;34(1):1247-1269.PMID:31914663DOI:10.1096/fj.201902163R.
Glycogen synthase kinase 3 (GSK3) was identified as an enzyme regulating sperm protein phosphatase. The GSK3α paralog, but not GSK3β, is essential for sperm function. Sperm lacking GSK3α display altered motility and are unable to undergo hyperactivation, which is essential for fertilization. Male mice lacking sperm-specific calcineurin (PP2B), a calcium regulated phosphatase, in testis and sperm, are also infertile. Loss of PP2B results in impaired epididymal sperm maturation and motility. The phenotypes of GSK3α and PP2B knockout mice are similar, prompting us to examine the interrelationship between these two enzymes in sperm. High calcium levels must exist to permit catalytically active calcineurin to function during epididymal sperm maturation. Total and free calcium levels are high in immotile compared to motile epididymal sperm. Inhibition of calcineurin by FK506 results in an increase in the net phosphorylation and a consequent decrease in catalytic activity of sperm GSK3. The inhibitor FK506 and an isoform-selective inhibitor of GSK3α, BRD0705, also inhibited fertilization of eggs in vitro. Interrelated functions of GSK3α and sperm PP2B are essential during epididymal sperm maturation and during fertilization. Our results should enable the development of male contraceptives targeting one or both enzymes.
Exploiting an Asp-Glu "switch" in glycogen synthase kinase 3 to design paralog-selective inhibitors for use in acute myeloid leukemia
Sci Transl Med 2018 Mar 7;10(431):eaam8460.PMID:29515000DOI:10.1126/scitranslmed.aam8460.
Glycogen synthase kinase 3 (GSK3), a key regulatory kinase in the wingless-type MMTV integration site family (WNT) pathway, is a therapeutic target of interest in many diseases. Although dual GSK3α/β inhibitors have entered clinical trials, none has successfully translated to clinical application. Mechanism-based toxicities, driven in part by the inhibition of both GSK3 paralogs and subsequent β-catenin stabilization, are a concern in the translation of this target class because mutations and overexpression of β-catenin are associated with many cancers. Knockdown of GSK3α or GSK3β individually does not increase β-catenin and offers a conceptual resolution to targeting GSK3: paralog-selective inhibition. However, inadequate chemical tools exist. The design of selective adenosine triphosphate (ATP)-competitive inhibitors poses a drug discovery challenge due to the high homology (95% identity and 100% similarity) in this binding domain. Taking advantage of an Asp133→Glu196 "switch" in their kinase hinge, we present a rational design strategy toward the discovery of paralog-selective GSK3 inhibitors. These GSK3α- and GSK3β-selective inhibitors provide insights into GSK3 targeting in acute myeloid leukemia (AML), where GSK3α was identified as a therapeutic target using genetic approaches. The GSK3α-selective compound BRD0705 inhibits kinase function and does not stabilize β-catenin, mitigating potential neoplastic concerns. BRD0705 induces myeloid differentiation and impairs colony formation in AML cells, with no apparent effect on normal hematopoietic cells. Moreover, BRD0705 impairs leukemia initiation and prolongs survival in AML mouse models. These studies demonstrate feasibility of paralog-selective GSK3α inhibition, offering a promising therapeutic approach in AML.