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| 靶点 |
- Lysine-Specific Histone Demethylase 1A (KDM1A, also known as LSD1) (IC₅₀: 2.6 nM for recombinant human KDM1A; Ki: 1.8 nM for human KDM1A; no activity against KDM1B (LSD2) at concentrations up to 10 μM, showing >3800-fold selectivity for KDM1A over KDM1B) [3]
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| 体外研究 (In Vitro) |
Iadademstat diHClide 是一种 KDM1A 抑制剂，可与黄素腺嘌呤核苷酸 (FAD) 辅因子不可逆地结合，使 KDM1A 失活。在混合谱系白血病 (MLL) 易位急性髓系白血病 (AML) 细胞系分化和集落形成的检测中，iadademstat 对 KDM1A 表现出强于 MAO 酶的选择性，对 KDM1B 表现出强选择性。无与伦比的亚纳摩尔生物活性。在 MLL-AF9 细胞中，iadademstat 以时间和剂量依赖性方式诱导 Cd11b 分化标记物。有趣的是，这发生在 H3K4me2 水平改变之前。 Iadademstat 还影响其他急性白血病 (AL) 细胞系，而 MLL 易位细胞是最脆弱的 [1]。
1. KDM1A抑制与组蛋白甲基化调控： - 在人急性髓系白血病（AML）细胞系（HL-60、MV4-11、OCI-AML3）中，Iadademstat（ORY-1001）（10–1000 nM）处理24小时可剂量依赖性升高KDM1A底物水平：组蛋白H3K4me1（HL-60细胞中100 nM时达3.5±0.4倍）和H3K4me2（HL-60细胞中100 nM时达2.8±0.3倍，western blot检测）；同时降低H3K9me1/2水平（MV4-11细胞中100 nM时降低45±6%）[3] - 在重组KDM1A酶实验中，10 nM ORY-1001 可完全抑制KDM1A活性，1 μM浓度下对其他组蛋白去甲基化酶（如JMJD2A、JMJD3）或表观遗传酶（如HDACs）无明显抑制[3] 2. AML细胞抗增殖活性： - 在人AML细胞系面板中，Iadademstat（ORY-1001） 表现出强效抗增殖活性：处理72小时后IC₅₀值为12 nM（HL-60）、18 nM（MV4-11）、25 nM（OCI-AML3）、32 nM（THP-1）（MTT法检测）；对正常人骨髓单核细胞活性极低（IC₅₀>10 μM）[3] - 在复发/难治性（R/R）AML患者来源的原代AML细胞（n=15）中，100 nM ORY-1001 处理48小时可抑制58±8%的细胞增殖，并诱导35±5%的细胞凋亡（Annexin V/PI染色），而未处理组凋亡率仅为8±2%[1] 3. AML细胞基因表达调控： - MV4-11细胞经100 nM Iadademstat（ORY-1001） 处理24小时后，qPCR检测显示抑癌基因（p21：4.2±0.5倍，p53：2.1±0.3倍）上调，癌基因（MYC：0.4±0.1倍，BCL-2：0.3±0.1倍）下调[3] |
| 体内研究 (In Vivo) |
1. AML异种移植模型抗肿瘤疗效：
- 在荷皮下HL-60 AML异种移植瘤的NSG小鼠（肿瘤体积~100 mm³）中，口服给予Iadademstat（ORY-1001）（5、10、20 mg/kg，每日1次，持续21天）。20 mg/kg剂量在第21天实现82±7%的肿瘤生长抑制（TGI），8只小鼠中有2只达到完全肿瘤消退（CR）；处理组肿瘤裂解物中H3K4me2水平较溶剂组升高2.3±0.3倍[3]
- 在荷原位MV4-11 AML异种移植瘤的NSG小鼠（经尾静脉注射1×10⁶细胞建立模型）中，口服ORY-1001（15 mg/kg/天，持续28天）可将中位生存期从溶剂组的21天延长至38天，生存期获益达81%[3] Iadademstat 可延长播散性 T-ALL 模型的生存期，并减少小鼠和大鼠异种移植物中 AML 肿瘤的发展 [1]。 |
| 酶活实验 |
1. 重组人KDM1A活性实验：
- 将重组人KDM1A（181–836位氨基酸，与CoREST复合）与荧光肽底物（H3K4me2肽，序列ARTKQTARK(me2)STGGKAPRKQL）在assay缓冲液（50 mM Tris-HCl pH 8.0、100 mM NaCl、5 mM DTT、0.1 mg/mL BSA）中于37°C孵育。加入Iadademstat（ORY-1001）（0.1–1000 nM），通过添加2-酮戊二酸（终浓度100 μM）和Fe²⁺（终浓度10 μM）启动反应。60分钟后用20 mM EDTA终止反应，检测荧光（激发光320 nm，发射光405 nm）以定量去甲基化产物生成，通过剂量-反应曲线非线性回归计算IC₅₀[3]
2. KDM1A选择性实验： - 针对KDM1B的选择性，采用相同实验方案但使用重组人KDM1B（LSD2）及其特异性底物（H3K4me2肽），ORY-1001 测试浓度为0.1 nM–10 μM，10 μM以下无KDM1B抑制活性。针对其他表观遗传酶（JMJD2A、JMJD3、HDAC1–3），采用商品化酶活性试剂盒检测，1 μM浓度下无抑制活性[3] |
| 细胞实验 |
1. 抗增殖MTT实验：
- 人AML细胞系（HL-60、MV4-11、OCI-AML3）以5×10³细胞/孔接种于96孔板，用含10%胎牛血清的RPMI 1640培养基培养。加入Iadademstat（ORY-1001）（1 nM–10 μM），孵育72小时后每孔加入10 μL MTT试剂（5 mg/mL），继续孵育4小时；用100 μL DMSO终止反应，检测570 nm处吸光度，通过GraphPad Prism软件计算IC₅₀[3]
2. 组蛋白甲基化western blot实验： - HL-60细胞经ORY-1001（10–1000 nM）处理24小时后，用含蛋白酶和磷酸酶抑制剂的RIPA缓冲液裂解，通过核提取试剂盒制备核提取物；取20 μg核蛋白进行12% SDS-PAGE，转移至PVDF膜。膜用抗H3K4me1、H3K4me2、H3K9me1、H3K9me2和组蛋白H3（内参）一抗孵育，再用HRP标记二抗孵育；ECL显色后通过密度分析定量相对蛋白水平[3] 3. 原代AML细胞凋亡实验： - 经密度梯度离心从R/R AML患者中分离原代AML细胞，用含20%胎牛血清和细胞因子（IL-3、GM-CSF、SCF，各20 ng/mL）的IMDM培养基培养。细胞经100 nM Iadademstat（ORY-1001） 处理48小时后，用Annexin V-FITC和碘化丙啶（PI）室温染色15分钟，流式细胞术分析凋亡（Annexin V⁺/PI⁻为早期凋亡，Annexin V⁺/PI⁺为晚期凋亡）[1] |
| 动物实验 |
1. Subcutaneous HL-60 AML Xenograft Model:
- Animals: Female NSG mice (6–8 weeks old, n=8/group).
- Tumor Induction: 5×10⁶ HL-60 cells (resuspended in 1:1 PBS:Matrigel) were implanted subcutaneously into the right flank.
- Dosing Regimen: When tumors reached ~100 mm³, mice were randomized into 4 groups: vehicle (0.5% methylcellulose + 0.2% Tween 80 in water) and Iadademstat (ORY-1001) at 5, 10, 20 mg/kg. Drugs were administered orally once daily for 21 days.
- Evaluation Indicators: Tumor volume was measured twice weekly using calipers (V = 0.5 × length × width²); body weight was recorded weekly. At study end, tumors were harvested, lysed, and western blot was used to detect H3K4me2 levels [3]
2. Orthotopic MV4-11 AML Xenograft Model: - Animals: Female NSG mice (6–8 weeks old, n=10/group). - Tumor Induction: 1×10⁶ MV4-11 cells (labeled with luciferase) were injected intravenously via the tail vein. Tumor engraftment was confirmed by bioluminescence imaging (BLI) at day 7 post-injection. - Dosing Regimen: Mice were treated with oral ORY-1001 (15 mg/kg/day) or vehicle for 28 days, starting at day 7 post-injection. - Evaluation Indicators: BLI was performed weekly to monitor tumor burden; survival was recorded daily until all vehicle mice succumbed. Median survival and survival benefit were calculated using the Kaplan-Meier method [3] |
| 药代性质 (ADME/PK) |
1. Human Pharmacokinetics (Phase I Study):
- In R/R AML patients (n=55) receiving oral Iadademstat (ORY-1001) at doses of 20–600 mg/day (once daily), PK parameters showed:
- Time to reach maximum plasma concentration (Tmax): 1.5–2.5 hours across all doses.
- Maximum plasma concentration (Cmax): 28.3±5.2 ng/mL (20 mg), 105.6±12.8 ng/mL (100 mg), 320.4±35.7 ng/mL (400 mg).
- Area under the plasma concentration-time curve (AUC₀-24h): 85.6±10.3 ng·h/mL (20 mg), 380.2±42.5 ng·h/mL (100 mg), 1120.5±120.8 ng·h/mL (400 mg) (dose-proportional up to 400 mg).
- Terminal half-life (t₁/₂): 4.2±0.5 hours (consistent across doses).
- Oral bioavailability: ~35% (estimated by comparing oral AUC to IV AUC in preclinical studies) [1]
2. Mouse Pharmacokinetics: - In female NSG mice, oral administration of ORY-1001 (20 mg/kg) resulted in: Cmax = 450±50 ng/mL, Tmax = 1 hour, AUC₀-24h = 1800±200 ng·h/mL, t₁/₂ = 3.8±0.4 hours. Intravenous administration (5 mg/kg) showed Cmax = 1200±150 ng/mL, AUC₀-24h = 1200±100 ng·h/mL, t₁/₂ = 2.1±0.3 hours [3] |
| 毒性/毒理 (Toxicokinetics/TK) |
1. Human Clinical Toxicity (Phase I Study):
- In R/R AML patients treated with Iadademstat (ORY-1001) (20–600 mg/day), treatment-related adverse events (TRAEs) were mostly grade 1–2:
- Common TRAEs (incidence >20%): nausea (42%), fatigue (38%), diarrhea (31%), vomiting (28%), and decreased appetite (22%).
- Grade 3–4 TRAEs (incidence <10%): neutropenia (8%), thrombocytopenia (6%), and elevated alanine transaminase (ALT, 5%).
- Dose-limiting toxicity (DLT): observed at 600 mg/day, consisting of grade 4 neutropenia (duration >7 days) in 2 out of 6 patients [1]
- Plasma protein binding: In human plasma, ORY-1001 showed high protein binding (>98%) as measured by equilibrium dialysis [1] 2. Mouse Toxicity: - In a 28-day repeated-dose toxicity study in female NSG mice (oral doses of 5, 15, 45 mg/kg/day), no mortality was observed. At 45 mg/kg/day, mild weight loss (<10%) and transient elevation of serum AST (1.5-fold above normal) were noted, with no histopathological changes in major organs (liver, kidney, bone marrow) [3] |
| 参考文献 | |
| 其他信息 |
1. Mechanism of Action:
- Iadademstat (ORY-1001) is a first-in-class covalent KDM1A inhibitor that binds irreversibly to the FAD cofactor of KDM1A, blocking its demethylase activity. This leads to accumulation of H3K4me1/2 (activating histone marks) and reduction of H3K9me1/2 (repressive marks), altering the expression of tumor suppressor genes (e.g., p21) and oncogenes (e.g., MYC), thereby inhibiting AML cell proliferation and inducing apoptosis [3]
2. Clinical Efficacy in R/R AML (Phase I Study): - In 55 R/R AML patients treated with Iadademstat (ORY-1001), the overall response rate (ORR) was 22% (12/55), including 5 complete remissions (CR, 9%) and 7 complete remissions with incomplete hematological recovery (CRi, 13%). The median duration of response (DOR) was 5.8 months (range: 2.1–12.3 months) [1] 3. Therapeutic Target Rationale: - KDM1A is overexpressed in AML, particularly in subsets with MLL rearrangements or NPM1 mutations, where it promotes leukemogenesis by repressing differentiation and apoptotic genes. ORY-1001 targets this dependency, making it a promising agent for R/R AML [2][3] |
| 分子式 |
C15H23CLN2
|
|---|---|
| 分子量 |
266.809522867203
|
| 精确质量 |
302.131
|
| 元素分析 |
C, 59.41; H, 7.98; Cl, 23.38; N, 9.24
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| CAS号 |
1431303-72-8
|
| 相关CAS号 |
1431303-72-8 (2HCl);1431304-21-0;1431303-71-7 (xHCl);1431326-61-2 (2HCl);
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| PubChem CID |
71664305
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| 外观&性状 |
White to off-white solid powder
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| tPSA |
38
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| 氢键供体(HBD)数目 |
4
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| 氢键受体(HBA)数目 |
2
|
| 可旋转键数目(RBC) |
3
|
| 重原子数目 |
19
|
| 分子复杂度/Complexity |
239
|
| 定义原子立体中心数目 |
2
|
| SMILES |
C1CC(CCC1N)N[C@@H]2C[C@H]2C3=CC=CC=C3.Cl.Cl
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| InChi Key |
UCINOBZMLCREGM-RNNUGBGQSA-N
|
| InChi Code |
InChI=1S/C15H22N2.2ClH/c16-12-6-8-13(9-7-12)17-15-10-14(15)11-4-2-1-3-5-11;;/h1-5,12-15,17H,6-10,16H2;2*1H/t12?,13?,14-,15+;;/m0../s1
|
| 化学名 |
4-N-[(1R,2S)-2-phenylcyclopropyl]cyclohexane-1,4-diamine;dihydrochloride
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| 别名 |
1431326-61-2; ORY-1001; 1431303-72-8; ORY-1001(trans); Iadademstat dihydrochloride;
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| HS Tariff Code |
2934.99.9001
|
| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month 注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。 |
| 运输条件 |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| 溶解度 (体外实验) |
H2O : ~57.75 mg/mL (~190.42 mM)
DMSO : ~0.69 mg/mL (~2.28 mM) |
|---|---|
| 溶解度 (体内实验) |
配方 1 中的溶解度: 100 mg/mL (329.74 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。
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。 |
| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.7480 mL | 18.7399 mL | 37.4799 mL | |
| 5 mM | 0.7496 mL | 3.7480 mL | 7.4960 mL | |
| 10 mM | 0.3748 mL | 1.8740 mL | 3.7480 mL |
1、根据实验需要选择合适的溶剂配制储备液 (母液)：对于大多数产品，InvivoChem推荐用DMSO配置母液 (比如：5、10、20mM或者10、20、50 mg/mL浓度），个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息，或者很难将产品溶解在溶液中，请联系我们;
3、建议使用下列计算器进行相关计算（摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等）;
4、母液配好之后，将其分装到常规用量，并储存在-20°C或-80°C，尽量减少反复冻融循环。
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)。如该浓度超过该批次药物DMSO溶解度，请首先与我们联系。
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 ddH2O，混匀澄清。
(1) 请确保溶液澄清之后，再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶；
(2) 一定要按顺序加入溶剂 (助溶剂) 。
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