SIM1
目录号 : GC63776
SIM1 是一种有效的 von Hippel-Lindau (VHL)-based PROTAC，能够对所有BET 家族成员进行降解，并优先降解 BRD2 (IC50=1.1 nM; Kd=186 nM)。SIM1显示出持续的抗癌活性。
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
SIM1 is a potent von Hippel-Lindau (VHL)-based trivalent PROTAC capable of degradation for all BET family members, with preference for BRD2 degradation (IC50=1.1 nM; Kd=186 nM). SIM1 shows sustained anti-cancer activity[1].
SIM1 (1 nM; 30 hours; MV4-11 cells) results in measurable cellular death after 6 hours[1].SIM1 (1 µM; 4 hours; HEK293 cells) degrades BET proteins[1].SIM1 induces conformational changes upon binding to the BET protein to simultaneously engage with high avidity both its bromodomains in a cis intramolecular fashion. SIM1 engages BD1 and BD2 intramolecularly and forms a 1:1:1 ternary complex with VHL and BRD4[1].
[1]. Satomi Imaide, et al. Trivalent PROTACs enhance protein degradation through cooperativity and avidity. Biological and Medicinal Chemistry.
| Cas No. | SDF | ||
| 分子式 | C79H98Cl2N14O13S3 | 分子量 | 1618.81 |
| 溶解度 | 储存条件 | Store at -20°C, protect from light, stored under nitrogen | |
| 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 | 0.6177 mL | 3.0887 mL | 6.1774 mL |
| 5 mM | 0.1235 mL | 0.6177 mL | 1.2355 mL |
| 10 mM | 0.0618 mL | 0.3089 mL | 0.6177 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。
Sim1-expressing cells illuminate the origin and course of migration of the nucleus of the lateral olfactory tract in the mouse amygdala
Brain Struct Funct 2021 Mar;226(2):519-562.PMID:33492553DOI:10.1007/s00429-020-02197-1.
We focus this report on the nucleus of the lateral olfactory tract (NLOT), a superficial amygdalar nucleus receiving olfactory input. Mixed with its Tbr1-expressing layer 2 pyramidal cell population (NLOT2), there are Sim1-expressing cells whose embryonic origin and mode of arrival remain unclear. We examined this population with Sim1-ISH and a Sim1-tauLacZ mouse line. An alar hypothalamic origin is apparent at the paraventricular area, which expresses SIM1 precociously. This progenitor area shows at E10.5 a Sim1-expressing dorsal prolongation that crosses the telencephalic stalk and follows the terminal sulcus, reaching the caudomedial end of the pallial amygdala. We conceive this Sim1-expressing hypothalamo-amygdalar corridor (HyA) as an evaginated part of the hypothalamic paraventricular area, which participates in the production of Sim1-expressing cells. From E13.5 onwards, Sim1-expressing cells migrated via the HyA penetrate the posterior pallial amygdalar radial unit and associate therein to the incipient Tbr1-expressing migration stream which swings medially past the amygdalar anterior basolateral nucleus (E15.5), crosses the pallio-subpallial boundary (E16.5), and forms the NLOT2 within the anterior amygdala by E17.5. We conclude that the Tbr1-expressing NLOT2 cells arise strictly within the posterior pallial amygdalar unit, involving a variety of required gene functions we discuss. Our results are consistent with the experimental data on NLOT2 origin reported by Remedios et al. (Nat Neurosci 10:1141-1150, 2007), but we disagree on their implication in this process of the dorsal pallium, observed to be distant from the amygdala.
SIM1 inhibits bone formation by enhancing the sympathetic tone in male mice
Endocrinology 2015 Apr;156(4):1408-15.PMID:25607894DOI:10.1210/en.2014-1872.
Single-minded 1 (SIM1) is a basic helix-loop-helix Per-Arnt-Sim transcription factor that is important for neuronal development in the hypothalamus. Loss-of-function mutation of SIM1 causes early-onset obesity. However, it is unknown whether and how SIM1 regulates bone remodeling. In this study, we found that adult-onset SIM1 deletion increases bone formation, leading to high bone mass. In contrast, Sim1-overexpressing transgenic mice exhibit decreased bone formation and low bone mass. SIM1 does not directly regulate osteoblastogenesis, because bone marrow mesenchymal stem cells from SIM1 mutant mice display a normal capacity for osteoblast differentiation. Instead, SIM1 inhibits bone formation via stimulating the sympathetic nervous system, because sympathetic tone is decreased by SIM1 deletion but increased by SIM1 overexpression. Treatment with the β-adrenergic agonist isoproterenol effectively reverses the high bone mass in Sim1-knockout mice. These findings reveal SIM1 as a critical yet previously unrecognized modulator of skeletal homeostasis that functions through a central relay.
Selective Survival of SIM1/MC4R Neurons in Diet-Induced Obesity
iScience 2020 May 22;23(5):101114.PMID:32438321DOI:10.1016/j.isci.2020.101114.
In the melanocortin pathway, melanocortin-4 receptor (MC4R) functions to control energy homeostasis. MC4R is expressed in a sub-population of SIM1 neurons (SIM1/MC4R neurons) and functions in hypothalamic paraventricular nuclei (PVN) to control food intake. Mapping sites of hypothalamic injury in obesity is essential to counteract the disease. In the PVN of male and female mice with diet-induced obesity (DIO) there is neuronal loss. However, the existing subpopulation of PVN SIM1/MC4R neurons is unchanged, but has a loss of mitochondria and MC4R protein. In mice of both sexes with DIO, dietary intervention to re-establish normal weight restores abundance of MC4R protein in SIM1/MC4R neurons and neurogenesis in the PVN. However, the number of non-Sim1/MC4R neurons in the PVN continues to remain decreased. Selective survival and recovery of SIM1/MC4R neurons after DIO suggests these neurons as preferential target to restore energy homeostasis and of therapy against obesity.
Postnatal SIM1 deficiency causes hyperphagic obesity and reduced Mc4r and oxytocin expression
J Neurosci 2010 Mar 10;30(10):3803-12.PMID:20220015DOI:10.1523/JNEUROSCI.5444-09.2010.
Single-minded 1 (SIM1) mutations are one of the few known causes of nonsyndromic monogenic obesity in both humans and mice. Although the role of SIM1 in the formation of the hypothalamus has been described, its postdevelopmental, physiological functions have not been well established. Here we demonstrate that postnatal CNS deficiency of SIM1 is sufficient to cause hyperphagic obesity. We conditionally deleted SIM1 after birth using CaMKII-Cre (alpha-calcium/calmodulin-dependent protein kinase II-Cre) lines to recombine a floxed SIM1 allele. Conditional SIM1 heterozygotes phenocopied germ line SIM1 heterozygotes, displaying hyperphagic obesity and increased length. We also generated viable conditional SIM1 homozygotes, demonstrating that adult SIM1 expression is not essential for mouse or neuron survival and revealing a dosage-dependent effect of SIM1 on obesity. Using stereological cell counting, we showed that the phenotype of both germ line heterozygotes and conditional SIM1 homozygotes was not attributable to global hypocellularity of the paraventricular nucleus (PVN) of the hypothalamus. We also used retrograde tract tracing to demonstrate that the PVN of germ line heterozygous mice projects normally to the dorsal vagal complex and the median eminence. Finally, we showed that conditional SIM1 homozygotes and germ line SIM1 heterozygotes exhibit a remarkable decrease in hypothalamic oxytocin (Oxt) and PVN melanocortin 4 receptor (Mc4r) mRNA. These results demonstrate that the role of SIM1 in feeding regulation is not limited to formation of the PVN or its projections and that the hyperphagic obesity in Sim1-deficient mice may be attributable to changes in the leptin-melanocortin-oxytocin pathway.
Metabolic Effects of Oxytocin
Endocr Rev 2020 Apr 1;41(2):121-145.PMID:31803919DOI:10.1210/endrev/bnz012.
There is growing evidence that oxytocin (OXT), a hypothalamic hormone well recognized for its effects in inducing parturition and lactation, has important metabolic effects in both sexes. The purpose of this review is to summarize the physiologic effects of OXT on metabolism and to explore its therapeutic potential for metabolic disorders. In model systems, OXT promotes weight loss by decreasing energy intake. Pair-feeding studies suggest that OXT-induced weight loss may also be partly due to increased energy expenditure and/or lipolysis. In humans, OXT appears to modulate both homeostatic and reward-driven food intake, although the observed response depends on nutrient milieu (eg, obese vs. nonobese), clinical characteristics (eg, sex), and experimental paradigm. In animal models, OXT is anabolic to muscle and bone, which is consistent with OXT-induced weight loss occurring primarily via fat loss. In some human observational studies, circulating OXT concentrations are also positively associated with lean mass and bone mineral density. The impact of exogenous OXT on human obesity is the focus of ongoing investigation. Future randomized, placebo-controlled clinical trials in humans should include rigorous, standardized, and detailed assessments of adherence, adverse effects, pharmacokinetics/pharmacodynamics, and efficacy in the diverse populations that may benefit from OXT, in particular those in whom hypothalamic OXT signaling may be abnormal or impaired (eg, individuals with SIM1 deficiency, Prader-Willi syndrome, or craniopharyngioma). Future studies will also have the opportunity to investigate the characteristics of new OXT mimetic peptides and the obligation to consider long-term effects, especially when OXT is given to children and adolescents. (Endocrine Reviews XX: XX - XX, 2020).