ADH-1 (0.2 mg/mL) 是 N-钙粘蛋白诱导的细胞运动的有效抑制剂，并抑制胰腺癌细胞中胶原蛋白 I 介导的改变。 ADH-1 在 0、0.1、0.2、0.5 和 1.0 mg/mL 时以剂量依赖性和 N-钙粘蛋白依赖性方式引起细胞凋亡 [1]。

ADH-1 (50 mg/kg) 直接抑制胰腺癌小鼠模型中的肿瘤发展和转移。在采用过表达 N-钙粘蛋白的 BxPC-3 细胞的胰腺癌原位模型中，ADH-1 抑制肿瘤细胞侵袭和转移 [1]。在大鼠主动脉环测定中，ADH-1 在所检测的水平上没有表现出抗血管生成活性，在 PC3 皮下异种移植肿瘤模型中也没有任何抗肿瘤潜力 [2]。当 ADH-1 给予异种移植物 A375 而不是 DM443 异种移植物时，AKT 丝氨酸 473 磷酸化程度更高。在两种异种移植物中，ADH-1 均略微下调 N-钙粘蛋白表达 [3]。

Protein Binding
ADH-1 binds to and inhibits N-cadherin.

[1]. ADH-1 suppresses N-cadherin-dependent pancreatic cancer progression. Int J Cancer. 2008 Jan 1;122(1):71-7.

[2]. ADH1, an N-cadherin inhibitor, evaluated in preclinical models of angiogenesis and androgen-independent prostate cancer. Anticancer Drugs. 2007 Jun;18(5):563-8.

[3]. Targeting N-cadherin increases vascular permeability and differentially activates AKT in melanoma. Ann Surg. 2015 Feb;261(2):368-77.

Adherex's biotechnology compound, ADH-1, targets N-cadherin, a protein present on certain tumor cells and established tumor blood vessels. ADH-1 is currently in clinical development in a combination program with a range of chemotherapeutic agents to investigate the synergistic effects noted in our preclinical models. At the end of 2006, the Company also completed patient enrollment in our single-agent Phase Ib/II and Phase II trials of ADH-1. Cadherins are cell adhesion and cell signaling molecules crucial to the development of tissues, organs and organisms. Agents that target and inhibit cadherin function have the potential to attack the progression of cancer at two distinct points: * Direct targeting of cadherins expressed on cancer cells may disturb cadherin-mediated signaling, leading to apoptosis (death) of cancer cells. * Cadherin inhibitors may exploit the inherent structural weaknesses of the tumor vasculature, causing angiolysis (disruption of blood vessels) and tumor damage. As many tumors become more aggressive, invasive, and malignant, researchers have found that N-cadherin is expressed in greater amounts, making it an important target for developing anti-cancer treatments. Poorly differentiated, highly invasive carcinomas are characterized by over-expression of N-cadherin (as opposed to E-cadherin). This change in primary cadherin expression causes the epithelial cells to lose their tightly adherent, polarized and well-defined shape and become loosely adherent, flattened and migratory. Such cadherin switching promotes properties such as dedifferentiation, local invasion and metastasis, leading to poor prognosis. ADH-1 may have utility in a wide variety of cancers as N-cadherin is overexpressed in a variety of tumors. As tumors progress to become higher grade, invasive and more metastatic, the frequency of N-cadherin expression generally rises.
ADH-1 is a small, cyclic pentapeptide vascular-targeting agent with potential antineoplastic and antiangiogenic activities. ADH-1 selectively and competitively binds to and blocks N-cadherin, which may result in disruption of tumor vasculature, inhibition of tumor cell growth, and the induction of tumor cell and endothelial cell apoptosis. N-cadherin, a cell- surface transmembrane glycoprotein of the cadherin superfamily of proteins involved in calcium-mediated cell-cell adhesion and signaling mechanisms; may be upregulated in some aggressive tumors and the endothelial cells and pericytes of some tumor blood vessels.

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Drug Indication
Investigated for use/treatment in breast cancer, cancer/tumors (unspecified), melanoma, ovarian cancer, and solid tumors.

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Mechanism of Action
While ADH-1 has a single molecular target, N-cadherin, we believe its anti-cancer effect results from two distinct mechanisms of action - apoptosis and tumor vessel angiolysis. N-cadherin appears to act as a tumor cell survival factor. In cell culture studies, inhibition of N-cadherin binding between tumor cells has been shown to cause apoptosis of tumor cells, we believe as a result of disrupting the cadherin-regulated cell survival signals. ADH-1 also appears to disrupt the blood vessels needed for cancerous tumors to grow and flourish, with hemorrhaging having been noted in both our clinical and preclinical studies. We believe the mechanism for this disruption is either a competitive inhibition of the binding of cadherins between the endothelial cells of the tumor blood wall or apoptosis in tumor cells that form a part of the blood vessel wall, each leading to leakage and rupture of these vessels. The latter involves the phenomenon of tumor "mosaicism," in which tumor cells form a portion of the vascular wall (along with the endothelial cells). Induction of cell death of these tumor cells would result in tumor vascular disruption.

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Pharmacodynamics
ADH-1 is a biotech compounds that targets N-cadherin, a protein present on certain tumor cells and established tumor blood vessels. Cadherins are cell adhesion and cell signaling molecules crucial to the development of tissues, organs and organisms. Agents that target and inhibit cadherin function have the potential to attack the progression of cancer at two distinct points: * Direct targeting of cadherins expressed on cancer cells may disturb cadherin-mediated signaling, leading to apoptosis (death) of cancer cells. * Cadherin inhibitors may exploit the inherent structural weaknesses of the tumor vasculature, causing angiolysis (disruption of blood vessels) and tumor damage. The compound is indicated for treatment of a variety of invasive carcinomas and ADH-1 has been shown to be synergistic with taxane-based chemotherapy in the systemic treatment of ovarian cancer xenografts.

C22H34N8O6S2

570.68

570.204

229971-81-7

ADH-1 trifluoroacetate;1135237-88-5

9916058

White to off-white solid powder

1.4±0.1 g/cm3

1183.4±65.0 °C at 760 mmHg

669.5±34.3 °C

0.0±0.3 mmHg at 25°C

1.619

-2.35

305.17

7

9

5

38

907

5

C[C@H]1C(=O)N[C@H](C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@H](C(=O)N1)CC2=CN=CN2)NC(=O)C)C(=O)N)C(C)C

FQVLRGLGWNWPSS-BXBUPLCLSA-N

InChI=1S/C22H34N8O6S2/c1-10(2)17-22(36)29-15(18(23)32)7-37-38-8-16(27-12(4)31)21(35)28-14(5-13-6-24-9-25-13)20(34)26-11(3)19(33)30-17/h6,9-11,14-17H,5,7-8H2,1-4H3,(H2,23,32)(H,24,25)(H,26,34)(H,27,31)(H,28,35)(H,29,36)(H,30,33)/t11-,14-,15-,16-,17-/m0/s1

(4R,7S,10S,13S,16R)-16-acetamido-13-(1H-imidazol-5-ylmethyl)-10-methyl-6,9,12,15-tetraoxo-7-propan-2-yl-1,2-dithia-5,8,11,14-tetrazacycloheptadecane-4-carboxamide

ADH-1; ADH 1; NSC729477; ADH1; Brand name: Exherin; Exherin free base;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： (1). 该产品在溶液状态不稳定，请现配现用。  (2). 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~250 mg/mL (~438.07 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (3.64 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (3.64 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (3.64 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。