Kinesore
目录号 : GC30147
Kinesore是KLC2-SKIP相互作用的抑制剂。
Cas No.:363571-83-9
Sample solution is provided at 25 µL, 10mM.
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | To examine the effect of kinesore in cells, HeLa cells are treated with 50 μM kinesore or vehicle control (0.1% DMSO) for 1 h[1]. |
References: [1]. Randall TS, et al. A small-molecule activator of kinesin-1 drives remodeling of the microtubule network. Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):13738-13743. | |
Kinesore is an inhibitor of the KLC2-SKIP Interaction.
Remarkably, in kinesore-treated cells, the microtubule network is entirely reorganized into a series of loops and bundles. In addition, the lysosomal compartment accumulates in a juxtanuclear position, where there are relatively few microtubules. At 50 μM kinesore, this phenotype is highly penetrant, with 95±2.4% (n=3, total of 200 cells) of cells exhibiting a reorganized nonradial microtubule network. In titration experiments, in cells treated for 1 h, this phenotype becomes apparent at a concentration of 25 μM kinesore, with relatively little effect at or below concentrations of 12.5 μM. The effect is reversible because a 2-h washout of kinesore from cells treated for 1 h led to the reestablishment of the radial microtubule array. This kinesore-induced reorganization of the microtubule network is observed in a panel of mammalian normal and cancer cell lines. In wild-type cells, 50 μM kinesore induces the remodeling of the microtubule network and the formation of extensive microtubule-rich projections. This phenotype is strongly suppressed in Kif5B knockout cells, confirming that microtubule remodeling induced by kinesore is dependent upon the presence of kinesin-1[1].
[1]. Randall TS, et al. A small-molecule activator of kinesin-1 drives remodeling of the microtubule network. Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):13738-13743.
| Cas No. | 363571-83-9 | SDF | |
| Canonical SMILES | O=C(N/N=C/C1=C(C)N(C2=CC=CC([N+]([O-])=O)=C2)C(C)=C1)C3=CC(Br)=C(O)C(Br)=C3 | ||
| 分子式 | C20H16Br2N4O4 | 分子量 | 536.17 |
| 溶解度 | DMSO : 125 mg/mL (233.14 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.8651 mL | 9.3254 mL | 18.6508 mL |
| 5 mM | 0.373 mL | 1.8651 mL | 3.7302 mL |
| 10 mM | 0.1865 mL | 0.9325 mL | 1.8651 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
A small-molecule activator of kinesin-1 drives remodeling of the microtubule network
The microtubule motor kinesin-1 interacts via its cargo-binding domain with both microtubules and organelles, and hence plays an important role in controlling organelle transport and microtubule dynamics. In the absence of cargo, kinesin-1 is found in an autoinhibited conformation. The molecular basis of how cargo engagement affects the balance between kinesin-1's active and inactive conformations and roles in microtubule dynamics and organelle transport is not well understood. Here we describe the discovery of kinesore, a small molecule that in vitro inhibits kinesin-1 interactions with short linear peptide motifs found in organelle-specific cargo adaptors, yet activates kinesin-1's function of controlling microtubule dynamics in cells, demonstrating that these functions are mechanistically coupled. We establish a proof-of-concept that a microtubule motor-cargo interface and associated autoregulatory mechanism can be manipulated using a small molecule, and define a target for the modulation of microtubule dynamics.
Mast cell granule motility and exocytosis is driven by dynamic microtubule formation and kinesin-1 motor function
Mast cells are tissue-resident immune cells that have numerous cytoplasmic granules which contain preformed pro-inflammatory mediators. Upon antigen stimulation, sensitized mast cells undergo profound changes to their morphology and rapidly release granule mediators by regulated exocytosis, also known as degranulation. We have previously shown that Rho GTPases regulate exocytosis, which suggests that cytoskeleton remodeling is involved in granule transport. Here, we used live-cell imaging to analyze cytoskeleton remodeling and granule transport in real-time as mast cells were antigen stimulated. We found that granule transport to the cell periphery was coordinated by de novo microtubule formation and not F-actin. Kinesore, a drug that activates the microtubule motor kinesin-1 in the absence of cargo, inhibited microtubule-granule association and significantly reduced exocytosis. Likewise, shRNA knock-down of Kif5b, the kinesin-1 heavy chain, also reduced exocytosis. Imaging showed granules accumulated in the perinuclear region after kinesore treatment or Kif5b knock-down. Complete microtubule depolymerization with nocodazole or colchicine resulted in the same effect. A biochemically enriched granule fraction showed kinesin-1 levels increase in antigen-stimulated cells, but are reduced by pre-treatment with kinesore. Kinesore had no effect on the levels of Slp3, a mast cell granule cargo adaptor, in the granule-enriched fraction which suggests that cargo adaptor recruitment to granules is independent of motor association. Taken together, these results show that granules associate with microtubules and are driven by kinesin-1 to facilitate exocytosis.