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PRMT5-IN-27

别名: AMG193; AMG-193
目录号: V75868 纯度: ≥98%
COA 产品数据 产品说明书 SDS
AMG-193 (PRMT5-IN-27; compound 481是 PRMT5 的抑制剂（阻断剂/拮抗剂）。
PRMT5-IN-27 CAS号: 2790567-82-5
产品类别: Histone Methyltransferase
产品仅用于科学研究，不针对患者销售
规格 价格
500mg
1g
Other Sizes
大包装询价
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产品描述
AMG-193 (PRMT5-IN-27; compound 481 是 PRMT5 的抑制剂（阻断剂/拮抗剂）。 PRMT5-IN-27 抑制 HCT116 细胞生长/增殖，IC 50 为 0.107 μM。
生物活性&实验参考方法
靶点
PRMT5
体外研究 (In Vitro)
AMG 193是第二代蛋白质精氨酸甲基转移酶5（PRMT5）抑制剂，靶向甲硫腺苷磷酸化酶（MTAP）无效肿瘤中PRMT5的MTA结合状态。PRMT5负责癌症中失调的细胞必需蛋白的甲基化和基因沉默，并在含有MTAP缺失的肿瘤中受到部分抑制，约15%的实体瘤发生这种情况[2]。
体内研究 (In Vivo)
第一代PRMT5抑制剂是不可容忍的，因为PRMT5的不加区分的抑制导致剂量限制性骨髓抑制。在临床前研究中，AMG 193通过进一步抑制PRMT5功能，同时保留正常功能，从而改善第一代分子，在MTAP无效模型中证明了选择性抗肿瘤活性。我们报告了正在进行的首次人体（FIH）研究中剂量增加的初步临床结果[2]。
动物实验
Methods: AMG193 was orally administered in continuous 28-day cycles to patients (pts) with advanced MTAP-null solid tumors. Dose escalation proceeded via a BLRM method. The primary objectives include safety, tolerability, and identification of the maximum tolerated dose (MTD). Secondary objectives include preliminary antitumor activity by investigator-assessed RECIST, pharmacokinetics (PK) and pharmacodynamic (PD) effects.[2]
Results: As of August 8, 2023, 47 pts with MTAP-null cancer (PDAC n = 10; NSCLC n = 6; CCA = 5; MESO n = 3; others n = 23) were enrolled in seven escalating cohorts. Five pts had DLTs, and exploration continues per protocol to identify the MTD. The most common TRAEs were nausea (45%), fatigue (26%), decreased appetite (17%), and vomiting (17%). Preliminary PK analyses showed dose-proportional systemic exposure with a half-life of 7–11 hrs. Among 31 pts who had at least one postbaseline scan, there were 5 with confirmed PRs [PDAC (–100%), ovarian Sertoli-Leydig (–59%), RCC (–58%), esophageal (–46%), and gallbladder cancer (–63%), 1 each], 14 with stable disease (including 9 with some degree of tumor shrinkage), and 12 with disease progression. All PRs were ongoing at the data cutoff with treatment durations of 140–275 days. PD effects demonstrated dose-dependent reduction in serum total SDMA levels and complete PRMT5 inhibition was confirmed in five pts with on-treatment biopsies spanning multiple dose levels. Exploratory analysis of changes in variant allele frequency by ctDNA demonstrated rapid treatment effects that was predictive and correlated with response.[2]
Conclusion: AMG 193 is an MTA-cooperative PRMT5 inhibitor designed to induce synthetic lethality in MTAP-null solid tumors while sparing hematologic toxicity. The initial results of the FIH study demonstrate proof-of-concept with encouraging signs of preliminary clinical activity without evidence of myelosuppression. Dose escalation continues to proceed to establish the MTD. AMG 193 has demonstrated promise as a potential new therapeutic for pts with tumors that have MTAP loss[2].
参考文献
[1]. AMG 193 Effective in Multiple Tumor Types. Cancer Discov. 2023 Dec 12;13(12):2492. doi: 10.1158/2159-8290.CD-NB2023-0079.
[2].Abstract PR006: Initial results from first-in-human study of AMG 193, an MTA-cooperative PRMT5 inhibitor, in biomarker-selected solid tumors. Mol Cancer Ther (2023) 22 (12_Supplement): PR006. https://doi.org/10.1158/1535-7163.TARG-23-PR006.
[3]. Shon Booker, et al. Prmts inhibitors. WO2022132914A1. 2022-06-23.
其他信息
The second-generation PRMT5 inhibitor AMG 193 (Amgen) yielded partial responses in patients with a variety of tumor types while avoiding the toxicity associated with such first-generation agents. Reported at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held October 11–15 in Boston, MA, the findings point to a possible treatment avenue for the 10% to 15% of patients who have MTAP-deleted solid tumors.
“PRMT5 is responsible for methylation and gene silencing of cell-essential proteins dysregulated in cancer,” explained Jordi Rodón, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, who presented the findings. But broadly targeting PRMT5, as researchers had learned, caused serious myelosuppression and other intolerable effects, necessitating a different plan of attack.
On the biology front, researchers knew that tumors with MTAP loss accumulate the metabolite MTA. “Interestingly,” Rodón continued, “MTA is a natural inhibitor of PRMT5, so tumors having MTAP loss accumulate MTA and have a partial inhibition of PRMT5. With chemical mastery, you can develop drugs that bind to PRMT5 only in the presence of MTA,” killing tumor cells while sparing healthy ones.
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That's the thinking behind the new class of drugs called MTA-cooperative PRMT5 inhibitors, of which AMG 193 is one. Another is Mirati's MRTX1719. Boston-based Tango Therapeutics, which has two MTA-cooperative PRMT5 inhibitors in early-stage trials, Kraków, Poland's Ryvu Therapeutics, and Shanghai, China's Abbisko Therapeutics presented preclinical research on their respective agents at the Molecular Targets conference as well.
Having demonstrated that AMG 193 exploits this tumor-specific vulnerability in preclinical studies, Rodón and his team enrolled 48 patients with advanced solid tumors into a first-in-human phase I trial of the agent. Ten patients had pancreatic adenocarcinoma, seven had non–small cell lung cancer, five had cholangiocarcinoma, and three had mesothelioma; the remaining 23 patients had other types of cancer. All the patients had already tried at least one other therapy, with one third having tried four or more.
Patients received one of seven doses of AMG 193, ranging from 40 mg to 1,600 mg a day, with those taking the higher doses seeing greater tumor shrinkage. Overall, of the 31 patients who received at least one scan after starting treatment, five—one each with esophageal, pancreatic, renal cell, gallbladder, and ovarian Sertoli-Leydig cell cancer—experienced a partial response. Fourteen others had stable disease, nine of whom experienced some tumor shrinkage.
Rodón reported that 39 patients (81.3%) experienced treatment-related adverse events (TRAE), most commonly nausea, fatigue, loss of appetite, and vomiting, and most often at the higher doses. Three patients discontinued treatment due to TRAEs. Rodón noted that AMG 193 didn't cause significant neutropenia or thrombocytopenia, which had proven problematic with first-generation PRMT5 inhibitors.
“The new class of MTA-cooperative PRMT5 inhibitors does appear promising,” said Pasi Jänne, MD, PhD, of Dana-Farber Cancer Institute in Boston, who has been involved in research on MRTX1719 (Cancer Discov 2023;11:2412–31).
“MTAP deletions are found across cancers, which is an advantage for this class of agents, as there are no approved targeted therapies for many cancers with MTAP deletions—for example mesotheliomas or pancreas cancers,” Jänne said. But because MTAP loss is found in so many malignancies, he cautioned that more patients need to be enrolled in this trial and in others “to get a true sense of activity.”
David Kwiatkowski, MD, PhD, of Brigham and Women's Hospital in Boston and Dana-Farber, who is also involved in the Mirati study, said he is “quite enthusiastic and optimistic” about the future of MTA-cooperative PRMT5 inhibitors. He has a patient with mesothelioma enrolled in a study of MRTX1719 who's had a “fabulous response. He's been on it for a year, tolerating it, and feeling good.”
In total, six of 18 evaluable patients in the phase I/II MRTX1719 study had confirmed responses to the drug.
Thanks to the preclinical and early clinical studies, the mechanism of action of MTA-cooperative PRMT5 inhibitors “has been validated,” Kwiatkowski continued. “This isn't just one drug, or one company. It's multiple drugs, multiple companies. It's exciting.” –Suzanne Rose.
Referencess: https://aacrjournals.org/cancerdiscovery/article/13/12/2492/731594/AMG-193-Effective-in-Multiple-Tumor-TypesAMG-193

*注: 文献方法仅供参考, InvivoChem并未独立验证这些方法的准确性
化学信息 & 存储运输条件
分子式
C22H19F3N4O3
分子量
444.406475305557
精确质量
444.14
CAS号
2790567-82-5
PubChem CID
164536956
外观&性状
White to light yellow solid powder
LogP
1.8
tPSA
90.6Ų
氢键供体(HBD)数目
1
氢键受体(HBA)数目
9
可旋转键数目(RBC)
2
重原子数目
32
分子复杂度/Complexity
688
定义原子立体中心数目
1
SMILES
C1COC[C@@H](N1C(=O)C2=NC=C3C(=C2)C4=C(COC4)C(=N3)N)C5=CC=C(C=C5)C(F)(F)F
InChi Key
BFEBTMFPRJPBTK-LJQANCHMSA-N
InChi Code
InChI=1S/C22H19F3N4O3/c23-22(24,25)13-3-1-12(2-4-13)19-11-31-6-5-29(19)21(30)17-7-14-15-9-32-10-16(15)20(26)28-18(14)8-27-17/h1-4,7-8,19H,5-6,9-11H2,(H2,26,28)/t19-/m1/s1
化学名
(4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone
别名
AMG193; AMG-193
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
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)
溶解度数据
溶解度 (体外实验)
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
溶解度 (体内实验)
注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。
注射用配方
(IP/IV/IM/SC等)
注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。
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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

口服配方
口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。
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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。
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 2.2502 mL 11.2509 mL 22.5017 mL
5 mM 0.4500 mL 2.2502 mL 4.5003 mL
10 mM 0.2250 mL 1.1251 mL 2.2502 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。

计算器
计算 重置

摩尔浓度计算器可计算特定溶液所需的质量、体积/浓度，具体如下：

  • 计算制备已知体积和浓度的溶液所需的化合物的质量
  • 计算将已知质量的化合物溶解到所需浓度所需的溶液体积
  • 计算特定体积中已知质量的化合物产生的溶液的浓度
使用摩尔浓度计算器计算摩尔浓度的示例如下所示：
假如化合物的分子量为350.26 g/mol，在5mL DMSO中制备10mM储备液所需的化合物的质量是多少？
  • 在分子量（MW）框中输入350.26
  • 在“浓度”框中输入10，然后选择正确的单位（mM）
  • 在“体积”框中输入5，然后选择正确的单位（mL）
  • 单击“计算”按钮
  • 答案17.513 mg出现在“质量”框中。以类似的方式，您可以计算体积和浓度。
计算 重置

稀释计算器可计算如何稀释已知浓度的储备液。例如，可以输入C1、C2和V2来计算V1，具体如下：

制备25毫升25μM溶液需要多少体积的10 mM储备溶液？
使用方程式C1V1=C2V2，其中C1=10mM，C2=25μM，V2=25 ml，V1未知：
  • 在C1框中输入10，然后选择正确的单位（mM）
  • 在C2框中输入25，然后选择正确的单位（μM）
  • 在V2框中输入25，然后选择正确的单位（mL）
  • 单击“计算”按钮
  • 答案62.5μL（0.1 ml）出现在V1框中
g/mol
计算 重置

分子量计算器可计算化合物的分子量 (摩尔质量)和元素组成，具体如下：

注：化学分子式大小写敏感：C12H18N3O4  c12h18n3o4
计算化合物摩尔质量（分子量）的说明：
  • 要计算化合物的分子量 (摩尔质量)，请输入化学/分子式，然后单击“计算”按钮。
分子质量、分子量、摩尔质量和摩尔量的定义：
  • 分子质量（或分子量）是一种物质的一个分子的质量，用统一的原子质量单位（u）表示。（1u等于碳-12中一个原子质量的1/12）
  • 摩尔质量（摩尔重量）是一摩尔物质的质量，以g/mol表示。
/
计算 重置

配液计算器可计算将特定质量的产品配成特定浓度所需的溶剂体积 (配液体积)

  • 输入试剂的质量、所需的配液浓度以及正确的单位
  • 单击“计算”按钮
  • 答案显示在体积框中
动物体内实验配方计算器（澄清溶液）
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）
第二步：请输入动物体内配方组成（配方适用于不溶/难溶于水的化合物），不同的产品和批次配方组成不同，如对配方有疑问，可先联系我们提供正确的体内实验配方。此外，请注意这只是一个配方计算器，而不是特定产品的确切配方。
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+
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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)。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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