CB-103
(Synonyms: 6-[4-(叔丁基)苯氧基]吡啶-3-胺) 目录号 : GC38745
An inhibitor of Notch signaling
Cas No.:218457-67-1
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >97.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
CB-103 is an inhibitor of Notch signaling.1 It binds to the b-trefoil domain (BTD) of recombination signal binding protein for immunoglobulin kappa J region (RBPJ) and inhibits the assembly of the RBPJ-Notch intracellular domain (NICD) transcription complex. CB-103 inhibits ligand-induced Notch signaling in HeLa cells expressing mouse Notch1, -2, -3, or -4 (IC50s = 1.5, 0.9, 1.1, and 2.9 ?M, respectively). It reduces expression of the Notch target genes HES1, MYC, and DTX1 in RPMI-8402 T cell acute lymphoblastic leukemia (T-ALL) cells. In vivo, CB-103 (25 mg/kg) reduces tumor volume and increases survival in an HCC-1187 mouse xenograft model.
1.Lehal, R., Zaric, J., Vigolo, M., et al.Pharmacological disruption of the Notch transcription factor complexProc. Natl. Acad. Sci. USA117(28)16292-16301(2020)
| Cas No. | 218457-67-1 | SDF | |
| 别名 | 6-[4-(叔丁基)苯氧基]吡啶-3-胺 | ||
| Canonical SMILES | NC1=CC=C(OC2=CC=C(C(C)(C)C)C=C2)N=C1 | ||
| 分子式 | C15H18N2O | 分子量 | 242.32 |
| 溶解度 | DMSO: 250 mg/mL (1031.69 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。 |
||
| 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 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 4.1268 mL | 20.6339 mL | 41.2677 mL |
| 5 mM | 0.8254 mL | 4.1268 mL | 8.2535 mL |
| 10 mM | 0.4127 mL | 2.0634 mL | 4.1268 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。
CB-103: A novel CSL-NICD inhibitor for the treatment of NOTCH-driven T-cell acute lymphoblastic leukemia: A case report of complete clinical response in a patient with relapsed and refractory T-ALL
EJHaem 2022 Jun 16;3(3):1009-1012.PMID:36051082DOI:10.1002/jha2.510.
Relapsed T cell acute lymphoblastic leukaemia (T-ALL) has a very poor prognosis. A 24-year-old patient with relapsed high-risk T-ALL (PTEN gene deletion; NOTCH1 mutation), was treated with the NOTCH inhibitor CB-103. Within 1 week of starting CB-103, the bone marrow was free of T-ALL blast infiltration (MRD+) and successfully underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Sequential samples of ctDNA to monitor the disease after allo-HSCT showed a decrease of circulating Notch1 and PTEN alterations. This is the first T-ALL patient treated with CB-103. The observed clinical response encourages further exploration of CB-103 in ALL.
Notch Inhibition in Cancer: Challenges and Opportunities
Chimia (Aarau) 2020 Oct 28;74(10):779-783.PMID:33115560DOI:10.2533/chimia.2020.779.
Notch is a key oncogenic pathway in several human cancers and to date, no targeted treatment of Notch activated cancers is available to patients. Therapeutic targeting of Notch has been an unresolved challenge due to severe on-target dose limiting toxicities associated with pan-Notch inhibition by either γ-secretase inhibitors or receptor/ligand targeting MAbs. At Cellestia Biotech, we have identified novel series of small molecule inhibitors of the Notch transcription complex. These molecules act as pan-Notch inhibitors and do not cause toxicities commonly associated with first- and second-generation Notch inhibitors currently tested in the clinic, thus providing a novel and unique opportunity to address a high unmet medical need. Our lead molecule, CB-103 is currently being investigated in Phase-1 dose escalation in cancer patients. Cellestia Biothech is further expanding its medicinal chemistry activities advancing the development of novel molecules for targeting transcription factors in cancer as well as non-cancer indications.
Pharmacological disruption of the Notch transcription factor complex
Proc Natl Acad Sci U S A 2020 Jul 14;117(28):16292-16301.PMID:32601208DOI:10.1073/pnas.1922606117.
Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance, and resistance to cancer therapy. Several strategies, such as monoclonal antibodies against Notch ligands and receptors, as well as small-molecule γ-secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Here, we report the discovery of an orally active small-molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T cell acute lymphoblastic leukemia and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest and apoptosis, thereby impairing proliferation, including in GSI-resistant human tumor cell lines with chromosomal translocations and rearrangements in Notch genes. CB-103 produces Notch loss-of-function phenotypes in flies and mice and inhibits the growth of human breast cancer and leukemia xenografts, notably without causing the dose-limiting intestinal toxicity associated with other Notch inhibitors. Thus, we describe a pharmacological strategy that interferes with Notch signaling by disrupting the Notch transcription complex and shows therapeutic potential for treating Notch-driven cancers.
Crenigacestat (LY3039478) inhibits osteogenic differentiation of human valve interstitial cells from patients with aortic valve calcification in vitro
Front Cardiovasc Med 2022 Sep 29;9:969096.PMID:36247471DOI:10.3389/fcvm.2022.969096.
Calcific aortic valve disease (CAVD) is one of the dangerous forms of vascular calcification. CAVD leads to calcification of the aortic valve and disturbance of blood flow. Despite high mortality, there is no targeted therapy against CAVD or vascular calcification. Osteogenic differentiation of valve interstitial cells (VICs) is one of the key factors of CAVD progression and inhibition of this process seems a fruitful target for potential therapy. By our previous study we assumed that inhibitors of Notch pathway might be effective to suppress aortic valve leaflet calcification. We tested CB-103 and crenigacestat (LY3039478), two selective inhibitors of Notch-signaling, for suppression of osteogenic differentiation of VICs isolated from patients with CAVD in vitro. Effect of inhibitors were assessed by the measurement of extracellular matrix calcification and osteogenic gene expression. For effective inhibitor (crenigacestat) we also performed MTT and proteomics study for better understanding of its effect on VICs in vitro. CB-103 did not affect osteogenic differentiation. Crenigacestat completely inhibited osteogenic differentiation (both matrix mineralization and Runx2 expression) in the dosages that had no obvious cytotoxicity. Using proteomics analysis, we found several osteogenic differentiation-related proteins associated with the effect of crenigacestat on VICs differentiation. Taking into account that crenigacestat is FDA approved for clinical trials for anti-tumor therapy, we argue that this drug could be considered as a potential inhibitor of cardiovascular calcification.
Targeting pathogenic mechanisms in marginal zone lymphoma: from concepts and beyond
Ann Lymphoma 2020 Sep 30;4:7.PMID:34667996DOI:10.21037/aol-20-20.
Marginal zone lymphoma (MZL) represents a group of three distinct though overlapping lymphoid malignancies that includes extranodal, nodal and splenic marginal lymphoma. MZL patients usually present an indolent clinical course, although the disease remains largely incurable, save early stage disease that might be irradiated. Therapeutic advances have been limited due to the small patient population, and have largely been adapted from other indolent lymphomas. Here, we discuss the numerous targets and pathways which may offer the prospect of directly inhibiting the mechanisms identified promoting and sustaining marginal zone lymphomagenesis. In particular, we focus on the agents that may have at least a theoretical application in the disease. Various dysregulated pathways converge to produce an overarching stimulation of nuclear factor κB (NF-κB) and the MYD88-IRAK4 axis, which can be thus leveraged or targeting B-cell receptor signaling through BTK inhibitors (such as ibrutinib, zanubrutinib, acalabrutinib) and PI3K inhibitors (such as idelalisib, copanlisib, duvelisib umbralisib) or via more novel agents in development such as MALT1 inhibitors, SMAC mimetics, NIK inhibitors, IRAK4 or MYD88 inhibitors. NOTCH signaling is also crucial for marginal zone cells, but no clinical data are available with NOTCH inhibitors such as the γ-secretase inhibitor PF-03084014 or the NICD inhibitor CB-103. The hypermethylation phenotype, the overexpression of the PRC2-complex or the presence of TET2 mutations reported in MZL subsets make epigenetic agents (demethylating agents, EZH2 inhibitors, HDAC inhibitors) also potential therapeutic tools for MZL patients.