UT-34
目录号 : GC62124
UT-34 is a potent, selective and orally bioavailable second-generation androgen receptor (AR) pan antagonist and degrader with IC50 of 203.46 nM, 80.78 nM and 94.17 nM for wild-type, T877A and W741L AR, respectively. UT-34 is a potential next-generation therapeutic for enzalutamide-resistant prostate cancer.
Cas No.:2168525-92-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
UT-34 is a potent, selective and orally bioavailable second-generation androgen receptor (AR) pan antagonist and degrader with IC50 of 203.46 nM, 80.78 nM and 94.17 nM for wild-type, T877A and W741L AR, respectively. UT-34 is a potential next-generation therapeutic for enzalutamide-resistant prostate cancer.
UT-34 inhibits the wild-type and LBD-mutant ARs comparably and inhibits the in vitro proliferation. UT-34 promotes a conformation that is distinct from the LBD-binding competitive antagonist enzalutamide and degrades the AR through the ubiquitin proteasome mechanism. UT-34 has a broad safety margin and exhibits no cross-reactivity with Gprotein-coupled receptor kinase and nuclear receptor family members.[1]
UT-34 inhibits the wild-type and LBD-mutant ARs comparably and inhibits the in vivo growth of enzalutamide-sensitive and -resistant prostate cancer xenografts. In preclinical models, UT-34 induces the regression of enzalutamide-resistant tumors at doses when the AR is degraded; but, at lower doses, when the AR is just antagonized, it inhibits, without shrinking, the tumors.[1]
[1] Suriyan Ponnusamy, et al. Clin Cancer Res. 2019 Nov 15;25(22):6764-6780.
| Cas No. | 2168525-92-4 | SDF | |
| 分子式 | C15H12F4N4O2 | 分子量 | 356.27 |
| 溶解度 | DMSO : 250 mg/mL (701.71 mM; Need ultrasonic) | 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 | 2.8069 mL | 14.0343 mL | 28.0686 mL |
| 5 mM | 0.5614 mL | 2.8069 mL | 5.6137 mL |
| 10 mM | 0.2807 mL | 1.4034 mL | 2.8069 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。
Orally Bioavailable Androgen Receptor Degrader, Potential Next-Generation Therapeutic for Enzalutamide-Resistant Prostate Cancer
Clin Cancer Res 2019 Nov 15;25(22):6764-6780.PMID:31481513DOI:10.1158/1078-0432.CCR-19-1458.
Purpose: Androgen receptor (AR)-targeting prostate cancer drugs, which are predominantly competitive ligand-binding domain (LBD)-binding antagonists, are inactivated by common resistance mechanisms. It is important to develop next-generation mechanistically distinct drugs to treat castration- and drug-resistant prostate cancers. Experimental design: Second-generation AR pan antagonist UT-34 was selected from a library of compounds and tested in competitive AR binding and transactivation assays. UT-34 was tested using biophysical methods for binding to the AR activation function-1 (AF-1) domain. Western blot, gene expression, and proliferation assays were performed in various AR-positive enzalutamide-sensitive and -resistant prostate cancer cell lines. Pharmacokinetic and xenograft studies were performed in immunocompromised rats and mice. Results: UT-34 inhibits the wild-type and LBD-mutant ARs comparably and inhibits the in vitro proliferation and in vivo growth of enzalutamide-sensitive and -resistant prostate cancer xenografts. In preclinical models, UT-34 induced the regression of enzalutamide-resistant tumors at doses when the AR is degraded; but, at lower doses, when the AR is just antagonized, it inhibits, without shrinking, the tumors. This indicates that degradation might be a prerequisite for tumor regression. Mechanistically, UT-34 promotes a conformation that is distinct from the LBD-binding competitive antagonist enzalutamide and degrades the AR through the ubiquitin proteasome mechanism. UT-34 has a broad safety margin and exhibits no cross-reactivity with G-protein-coupled receptor kinase and nuclear receptor family members. Conclusions: Collectively, UT-34 exhibits the properties necessary for a next-generation prostate cancer drug.
Pyrazol-1-yl-propanamides as SARD and Pan-Antagonists for the Treatment of Enzalutamide-Resistant Prostate Cancer
J Med Chem 2020 Nov 12;63(21):12642-12665.PMID:33095584DOI:10.1021/acs.jmedchem.0c00943.
We report herein the design, synthesis, and pharmacological characterization of a library of novel aryl pyrazol-1-yl-propanamides as selective androgen receptor degraders (SARDs) and pan-antagonists that exert broad-scope AR antagonism. Pharmacological evaluation demonstrated that introducing a pyrazole moiety as the B-ring structural element in the common A-ring-linkage-B-ring nonsteroidal antiandrogens' general pharmacophore allowed the development of a new scaffold of small molecules with unique SARD and pan-antagonist activities even compared to our recently published AF-1 binding SARDs such as UT-155 (9) and UT-34 (10). Novel B-ring pyrazoles exhibited potent AR antagonist activities, including promising distribution, metabolism, and pharmacokinetic properties, and broad-spectrum AR antagonist properties, including potent in vivo antitumor activity. 26a was able to induce an 80% tumor growth inhibition of xenografts derived from the enzalutamide-resistant (Enz-R) VCaP cell line. These results represent an advancement toward the development of novel AR antagonists for the treatment of Enz-R prostate cancer.
Identification of tissue-specific vasculogenic cells originating from murine uterus
Histochem Cell Biol 2006 Jun;125(6):625-35.PMID:16311738DOI:10.1007/s00418-005-0113-x.
Endometrium is a highly regenerative adult tissue that undergoes repeated degeneration and regeneration following menarche. Therefore, it is believed that endometrium contains stem and/or progenitor cells in order to compensate for the regeneration of tissue components. We report here that stem-like cells having vasculogenic potential are present in the uterus. Enzymatically extracted cells from murine uteri were characterized and fractionated into four subpopulations by flowcytometry; CD34(+)/45(-) (UT-34), CD34(-)/45(-) (Ut-DN) and the remaining CD45(+) cell fractions (CD34(+)/45(+) and CD34(-)/45(+) cells). The UT-34 and Ut-DN fractions were mostly negative for putative endothelial cell (EC) markers, such as CD31, Flk-1, c-kit and VE-cadherin, although the Ut-DN fraction contained 2.8% CD31(+) cells. Ut-DN cells were further divided into CD31(+) and CD31(-) fractions. Three cell populations were obtained from green fluorescence protein (GFP) transgenic mice and were transplanted into injured wild-type mouse skeletal muscle. At 4 weeks after cell transplantation, donor-derived vascular smooth muscle and ECs were observed in the injured recipient muscle. A similar trend was observed in the UT-34 group, but differentiation into vascular smooth muscle was predominant. In contrast, the Ut-DN/31(+) cell-transplanted group showed preferential differentiation into vascular ECs, thus suggesting that they were relatively committed preexisting ECs. These characteristics were also seen in vitro, in clonal cell cultures. Interestingly, donor derived Ut-DN/31(+), Ut-DN/31(-) and UT-34 cells could not be identified after bone marrow (BM) transplantation, thus confirming that they are not derived from BM. It therefore appeared that tissue-specific vasculogenic cells are present in the murine uterus and that they exhibit vascular formation, even in different tissue microenvironments.
Exploration and Biological Evaluation of Basic Heteromonocyclic Propanamide Derivatives as SARDs for the Treatment of Enzalutamide-Resistant Prostate Cancer
J Med Chem 2021 Aug 12;64(15):11045-11062.PMID:34269581DOI:10.1021/acs.jmedchem.1c00439.
A series of propanamide derivatives were designed, synthesized, and pharmacologically characterized as selective androgen receptor degraders (SARDs) and pan-antagonists that exert a broad-scope androgen receptor (AR) antagonism. Incorporating different basic heteromonocyclic B-ring structural elements in the common A-ring-linkage-B-ring nonsteroidal antiandrogen general pharmacophore contributed to a novel scaffold of small molecules with SARD and pan-antagonist activities even compared to our recently published AF-1 binding SARDs such as UT-69 (11), UT-155 (12), and UT-34 (13). Compound 26f exhibited inhibitory and degradation effects in vitro in a wide array of wtAR, point mutant, and truncation mutant-driven prostate cancers (PCs). Further, 26f inhibited tumor cell growth in a xenograft model composed of enzalutamide-resistant (EnzR) LNCaP cells. These results demonstrate an advancement toward the development of novel SARDs and pan-antagonists with efficacy against EnzR prostate cancers.