CDK9/cyc T2 (Ki = 0.626 nM); CDK9/CycT1 (Ki = 1.68 nM); CDK6/cycD1 (Ki = 2.92 nM); CDK4/Cyc D1 (Ki = 3.96 nM); CDK1/cycB (Ki = 5.4 nM); CDK1/cyc A (Ki = 9.1 nM)

Voruciclib（0.5-5 µM；6 小时）显示 ABC 和 GCB 亚型中 MCL-1 的靶向下调[1]。细胞活力测定[1] 细胞系：U2932、RIVA、OCI-LY10 细胞（ABC 亚型）、NU-DHL-1、SU-DHL-4、SU-DHL-6 细胞（GCB 亚型） 浓度：0.5 µM，1 µM、2 µM、3 µM、4 µM、5 µM 孵育时间：6 小时 结果：在 ABC 和 GCB 亚型中均显示 MCL-1 的靶向下调。

盐酸 Voruciclib（200 mpk；口服强饲）与 Venetoclax（U2932、RIVA、SU-DHL-4 和 NU-DHL-1 中分别为 10 mpk、1 mpk、50 mpk、25 mpk）组合可增强肿瘤生长抑制作用在 U2932、RIVA、SU-DHL-4（每周 6 天，持续 4 周）和 NU-DHL-1 模型（每周 5 天，持续 3 周）DLBCL 模型中，与单独使用任一药物相比[1]。动物模型：ABC 亚型（U2932、RIVA、OCI-LY10）、GCB 亚型（SU-DHL-4、NU-DHL-1）异种移植到雌性 NOD.CB17-Prkdcscid/NCrHsd 小鼠中剂量：200 mpk 给药方式：口服强饲； U2932、RIVA、SU-DHL-4（每周 6 天，持续 4 周）、OCI-LY10（每周 6 天，持续 2 周）、NU-DHL-1（每周 5 天，持续 3 周） 结果：肿瘤增强除 OCI-LY10 模型外，U2932、RIVA、SU-DHL-4 和 NU-DHL-1 模型中的生长抑制。

生物信息学研究进展[1][br] 反应生物学公司测定了48种激酶对盐酸voruciclib的敏感性等级，以放射性γ-33P-ATP为磷酸供体，采用过滤结合法测定激酶活性。各激酶的ATP浓度接近Km值。对于每个激酶，从试验品的10点浓度曲线计算IC50值并转换为Ki值。本文研究的48种激酶在先前的筛选实验中被确定为最有希望的靶标候选。

细胞系：U2932、RIVA、OCI-LY10 细胞（ABC 亚型）、NU-DHL-1、SU-DHL-4、SU-DHL-6 细胞（GCB 亚型）
浓度：0.5 µM、1 µM、2 µM、3 µM、4 µM、5 µM
孵育时间：6 小时
结果：在 ABC 和 GCB 亚型中均显示 MCL-1 的靶向下调。

ABC subtypes (U2932, RIVA, OCI-LY10), GCB subtypes (SU-DHL-4, NU-DHL-1) xenografted in Female NOD.CB17-Prkdcscid/NCrHsd mice
200 mpk
Oral gavage; U2932, RIVA, SU-DHL-4 (six days per week for 4 weeks), OCI-LY10 (six days per week for 2 weeks), NU-DHL-1 (five days per week for 3 weeks)

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For systemic drug efficacy studies, mice were enrolled when tumors reached an average volume of 150–200 mm3. Assignment to treatment groups was carried out via stratified randomization. Tumor dimensions were measured twice a week using digital calipers along with recording of body weight. Tumor volume was calculated using formula V = π/6 (length x width x height) in mm3 . Animals were removed from the study when either any one of the three measured dimensions of the tumor exceeded 2 cm, volume exceeded 2000 mm3, ulceration was observed or if body weight loss greater than 20% was recorded. Drug formulations: voruciclib was formulated in 0.1% methylcellulose and venetoclax in 60% phosal 50, 30% PEG 400, 10% ethanol, both administered orally. Control cohorts were administered vehicles of both drugs, and each single agent cohort was administered the vehicle of the other drug. Depending on the assigned treatment, venetoclax (or its vehicle) was followed by voruciclib (or its vehicle) with 30 mins in between administrations to allow for gastric clearance as per veterinary recommendation. Model specific dosing regimens: U2932: venetoclax at 10 mpk twice a week, voruciclib 200 mpk six days per week for a total duration of 4 weeks; RIVA: venetoclax at 1 mpk twice a week, voruciclib 200 mpk six days per week for a total duration of four weeks; OCI-LY10: venetoclax at 25 mpk twice a week, voruciclib 200 mpk six days per week for a total duration of two weeks; NU-DHL-1: venetoclax at 50 mpk once a week, voruciclib at 200 mpk five days per week for a total duration of three weeks; SU-DHL-4: venetoclax at 25 mpk and voruciclib 200 mpk both six days per week for a total duration of four weeks. The venetoclax + voruciclib combination treatment cohort for each model received both drugs at the same doses and frequencies as the corresponding single agents.

[1]. Voruciclib, a clinical stage oral CDK9 inhibitor, represses MCL-1 and sensitizes high-risk Diffuse Large B-cell Lymphoma to BCL2 inhibition. Sci Rep. 2017 Dec 21;7(1):18007.

Voruciclib is under investigation in clinical trial NCT03547115 (A Phase 1 Study of Voruciclib in Subjects With B-Cell Malignancies or AML).
Voruciclib is a cyclin-dependent kinase (CDK) inhibitor with potential antineoplastic activity. Upon administration, voruciclib selectively inhibits cyclin-dependent kinase 4 (CDK4) and 6 (CDK6). This inhibits retinoblastoma (Rb) protein phosphorylation early in the G1 phase, which prevents CDK-mediated G1-S phase transition and leads to cell cycle arrest. This suppresses DNA replication and decreases tumor cell proliferation. CDK4 and 6 are serine/threonine kinases that are upregulated in many tumor cell types and play a key role in the regulation of cell cycle progression.

C22H19CLF3NO5

469.8412

469.09

C, 56.24; H, 4.08; Cl, 7.55; F, 12.13; N, 2.98; O, 17.03

1000023-04-0

Voruciclib hydrochloride;1000023-05-1;(2S,3R)-Voruciclib hydrochloride;rel-(2S,3R)-Voruciclib;1253731-24-6; 1000023-04-0; 2505206-37-9 (malonate)

67409219

Light yellow to yellow solid powder

4.261

94.14

3

9

3

32

750

2

ClC1C=C(C(F)(F)F)C=CC=1C1=CC(C2=C(C=C(C(=C2O1)[C@@H]1CCN(C)[C@@H]1CO)O)O)=O

MRPGRAKIAJJGMM-OCCSQVGLSA-N

InChI=1S/C22H19ClF3NO5/c1-27-5-4-12(14(27)9-28)19-15(29)7-16(30)20-17(31)8-18(32-21(19)20)11-3-2-10(6-13(11)23)22(24,25)26/h2-3,6-8,12,14,28-30H,4-5,9H2,1H3/t12-,14+/m1/s1

2-[2-chloro-4-(trifluoromethyl)phenyl]-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one

Voruciclib; 1000023-04-0; Voruciclib [INN]; P1446A-05; 2-[2-chloro-4-(trifluoromethyl)phenyl]-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one; W66XP666AM; CHEMBL3905910; P-1446;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO: ~50 mg/mL (~106.4 mM)

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。

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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)

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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

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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。

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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。