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 盐酸盐（0.5–5 µM；6 小时）可靶向下调 ABC 和 GCB 亚型中的 MCL-1 [1]。每个靶标（例如 CDK9/cyc T2、CDK9/cyc T1、CDK6/cyc D1、CDK4/cyc D1、CDK1/cyc B 和 CDK1/cyc）的 Ki 值分别为 0.626 nM、1.68 nM、2.92 nM A 代表 Voruciclib 盐酸盐）[1]。

Voruciclib 盐酸盐（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）联合增强肿瘤生长抑制U2932、RIVA、SU-DHL-4（每周 6 天，持续 4 周）和 NU-DHL-1（每周 5 天，持续 3 周）DLBCL 模型，与单独使用任一药物进行比较 [1]。

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。

Western Blot 分析[1]
细胞类型：U2932、RIVA、OCI-LY10 细胞（ABC 亚型）、NU-DHL-1、SU-DHL-4、SU-DHL-6 细胞（GCB 亚型）
测试浓度： 0.5 µM、1 µM、2 µM、3 µM、4 µM、5 µM
孵育持续时间： 6 小时（ hrs（小时））
实验结果：在 ABC 和 GCB 亚型中均显示出 MCL-1 的靶向下调。

Animal/Disease Models: ABC isoforms (U2932, RIVA, OCI-LY10), GCB isoforms (SU-DHL-4, NU-DHL-1) xenografted into female NOD.CB17-Prkdcscid/NCrHsd mice [1]
Doses: 200 mpk
Doses: po (oral gavage); U2932, RIVA, SU-DHL-4 (6 days per week for 4 weeks), OCI-LY10 (6 days per week for 2 weeks), NU-DHL-1 ( 5 days per week for 3 weeks)
Experimental Results: Tumor enhanced growth inhibition in U2932, RIVA, SU-DHL-4 and NU-DHL-1 models in addition to OCI-LY10 model.

[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.

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Aberrant regulation of BCL-2 family members enables evasion of apoptosis and tumor resistance to chemotherapy. BCL-2 and functionally redundant counterpart, MCL-1, are frequently over-expressed in high-risk diffuse large B-cell lymphoma (DLBCL). While clinical inhibition of BCL-2 has been achieved with the BH3 mimetic venetoclax, anti-tumor efficacy is limited by compensatory induction of MCL-1. Voruciclib, an orally bioavailable clinical stage CDK-selective inhibitor, potently blocks CDK9, the transcriptional regulator of MCL-1. Here, we demonstrate that voruciclib represses MCL-1 protein expression in preclinical models of DLBCL. When combined with venetoclax in vivo, voruciclib leads to model-dependent tumor cell apoptosis and tumor growth inhibition. Strongest responses were observed in two models representing high-risk activated B-cell (ABC) DLBCL, while no response was observed in a third ABC model, and intermediate responses were observed in two models of germinal center B-cell like (GCB) DLBCL. Given the range of responses, we show that CIVO, a multiplexed tumor micro-dosing technology, represents a viable functional precision medicine approach for differentiating responders from non-responders to BCL-2/MCL-1 targeted therapy. These findings suggest that the combination of voruciclib and venetoclax holds promise as a novel, exclusively oral combination therapy for a subset of high-risk DLBCL patients.[1]

C₂₂H₂₀CL₂F₃NO₅

506.30

505.067

1000023-05-1

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

67409218

Typically exists as Light yellow to yellow solid at room temperature

5.063

94.14

4

9

3

33

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.Cl

QCWRANLELLMJSH-OJMBIDBESA-N

InChI=1S/C22H19ClF3NO5.ClH/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;1H/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;hydrochloride

Voruciclib hydrochloride; 1000023-05-1; Voruciclib (hydrochloride); UNII-8BEP29W01U; 8BEP29W01U; 2-[2-chloro-4-(trifluoromethyl)phenyl]-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one;hydrochloride; 4H-1-Benzopyran-4-one, 2-(2-chloro-4-(trifluoromethyl)phenyl)-5,7-dihydroxy-8-((2R,3S)-2-(hydroxymethyl)-1-methyl-3-pyrrolidinyl)-, hydrochloride (1:1); 4H-1-Benzopyran-4-one, 2-[2-chloro-4-(trifluoromethyl)phenyl]-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methyl-3-pyrrolidinyl]-, hydrochloride (1:1);

2934.99.9001

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。

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 (~493.78 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (4.11 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 (4.11 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 (4.11 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。