BRD9876
(Synonyms: 6-叔丁基-2,3-二氰基萘) 目录号 : GC48901An Eg5 inhibitor
Cas No.:32703-82-5
Sample solution is provided at 25 µL, 10mM.
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BRD9876 is an inhibitor of the kinesin spindle protein Eg5.1 It arrests Eg5-mediated microtubule gliding, as well as inhibits Eg5 ATPase activity in the presence of microtubules, in cell-free assays. BRD9876 is cytotoxic to MM.1S stroma-independent multiple myeloma cells (IC50 = 2.2 µM). It induces cell cycle arrest at the G2/M phase in MM.1S cells when used at a concentration of 10 µM.
1.Chattopadhyay, S., Stewart, A.L., Mukherjee, S., et al.Niche-based screening in multiple myeloma identifies a kinesin-5 inhibitor with improved selectivity over hematopoietic progenitorsCell Rep.10(5)755-770(2015)
Cas No. | 32703-82-5 | SDF | |
别名 | 6-叔丁基-2,3-二氰基萘 | ||
Canonical SMILES | N#CC1=CC2=CC=C(C(C)(C)C)C=C2C=C1C#N | ||
分子式 | C16H14N2 | 分子量 | 234.3 |
溶解度 | Chloroform: 10 mg/ml,DMF: 1 mg/ml,DMF:PBS (pH 7.2) (1:2): 0.33 mg/ml | 储存条件 | -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 4.268 mL | 21.3402 mL | 42.6803 mL |
5 mM | 0.8536 mL | 4.268 mL | 8.5361 mL |
10 mM | 0.4268 mL | 2.134 mL | 4.268 mL |
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2.
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Eg5 Inhibitors Have Contrasting Effects on Microtubule Stability and Metaphase Spindle Integrity
ACS Chem Biol 2017 Apr 21;12(4):1038-1046.PMID:28165699DOI:10.1021/acschembio.6b01040.
To uncover their contrasting mechanisms, antimitotic drugs that inhibit Eg5 (kinesin-5) were analyzed in mixed-motor gliding assays of kinesin-1 and Eg5 motors in which Eg5 "braking" dominates motility. Loop-5 inhibitors (monastrol, STLC, ispinesib, and filanesib) increased gliding speeds, consistent with inducing a weak-binding state in Eg5, whereas BRD9876 slowed gliding, consistent with locking Eg5 in a rigor state. Biochemical and single-molecule assays demonstrated that BRD9876 acts as an ATP- and ADP-competitive inhibitor with 4 nM KI. Consistent with its microtubule polymerase activity, Eg5 was shown to stabilize microtubules against depolymerization. This stabilization activity was eliminated in monastrol but was enhanced by BRD9876. Finally, in metaphase-arrested RPE-1 cells, STLC promoted spindle collapse, whereas BRD9876 did not. Thus, different Eg5 inhibitors impact spindle assembly and architecture through contrasting mechanisms, and rigor inhibitors may paradoxically have the capacity to stabilize microtubule arrays in cells.
Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors
Cell Rep 2015 Feb 10;10(5):755-770.PMID:25660025DOI:10.1016/j.celrep.2015.01.017.
Novel therapeutic approaches are urgently required for multiple myeloma (MM). We used a phenotypic screening approach using co-cultures of MM cells with bone marrow stromal cells to identify compounds that overcome stromal resistance. One such compound, BRD9876, displayed selectivity over normal hematopoietic progenitors and was discovered to be an unusual ATP non-competitive kinesin-5 (Eg5) inhibitor. A novel mutation caused resistance, suggesting a binding site distinct from known Eg5 inhibitors, and BRD9876 inhibited only microtubule-bound Eg5. Eg5 phosphorylation, which increases microtubule binding, uniquely enhanced BRD9876 activity. MM cells have greater phosphorylated Eg5 than hematopoietic cells, consistent with increased vulnerability specifically to BRD9876's mode of action. Thus, differences in Eg5-microtubule binding between malignant and normal blood cells may be exploited to treat multiple myeloma. Additional steps are required for further therapeutic development, but our results indicate that unbiased chemical biology approaches can identify therapeutic strategies unanticipated by prior knowledge of protein targets.