Cdk4/cyclin D1 (IC50 = 2 nM); CDK6/cyclinD1 (IC50 = 10 nM); CDK9/cyclinT1 (IC50 = 57 nM); CDK5/p35 (IC50 = 287 nM); Cdk5/p25 (IC50 = 355 nM); CDK2/cyclinE (IC50 = 504 nM); CDK7/Mat1/cyclinH1 (IC50 = 3910 nM); CDK1/cyclinB1 (IC50 = 1627 nM); PIM1 (IC50 = 39 nM); PIM2 (IC50 = 3400 nM); HIPK2 (IC50 = 31 nM); DYRK2 (IC50 = 61 nM); CK2 (IC50 = 117 nM); GSK3b (IC50 = 192 nM); JNK3 (IC50 = 389 nM); FLT3 (D835Y) (IC50 = 403 nM); FLT3 (IC50 = 3960 nM); DRAK1 (IC50 = 659 nM)

体外活性：Abemaciclib（以前称为 LY2835219）是一种有效、选择性、口服的 CDK4（细胞周期蛋白依赖性激酶）和 CDK6 双重抑制剂，在无细胞测定中 IC50 分别为 2 nM 和 10 nM。 LY2835219 特异性抑制 CDK4 和 6，从而抑制 G1 早期视网膜母细胞瘤 (Rb) 蛋白磷酸化。抑制 Rb 磷酸化可阻止 CDK 介导的 G1-S 相变，从而将细胞周期阻滞在 G1 期，抑制 DNA 合成并抑制癌细胞生长。丝氨酸/苏氨酸激酶 CDK4/6 的过度表达可导致细胞周期失调，如某些类型的癌症中所见。激酶测定：将细胞 (5 × 103) 铺在 96 孔板中。第二天将细胞处理 24 至 48 小时，然后根据制造商的说明和发光板读数器，通过 Caspase-Glo-3/7 测定法评估 caspase-3 活性。细胞测定：将细胞接种到 96 孔板中，使其粘附过夜，并用 DMSO 对照 (0.1% v/v) 或指定化合物处理 72 小时。根据制造商的说明，使用细胞计数试剂盒测定细胞活力和增殖。使用 CompuSyn 确定 LY2835219 和 mTOR 抑制剂之间的相互作用。组合指数 (CI) 值为 1 表示药物相互作用相加，而 CI < 1 表示协同作用，CI > 1 表示拮抗作用。

LY2835219 使 BBB 流出饱和，未结合血浆 IC50 约为 95 nM。 LY2835219-MsOH 在大脑中的剂量百分比为 0.5–3.9%。在皮下和颅内人胶质母细胞瘤模型 (U87MG) 中，LY2835219-MsOH 作为单一药物以及与替莫唑胺联合使用，均以剂量依赖性方式抑制肿瘤生长。

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Abemaciclib单药治疗导致肿瘤生长延迟，这与肿瘤中T细胞炎症特征增加有关。联合抗pd - l1治疗可导致肿瘤完全消退和免疫记忆，并伴有抗原呈递增强、T细胞炎症表型和细胞周期控制增强。[3]

LY2835219 (abemaciclib)是由礼来公司研究实验室的科学家通过化合物和生化筛选鉴定出来的，并因其生物活性和对CDK4/ cyclin D1复合物(IC50 =2 nmol/L)和CDK6/cyclin D1复合物(IC50 =10 nmol/L)的高度选择性抑制而被选中，在纳摩尔范围内对其他CDK/cyclin复合物或细胞周期相关激酶没有活性，除了CDK9的IC50至少高出5倍(图2)23该化合物被证明是CDK4和CDK6的atp结合域的竞争性抑制剂，对CDK4的抑制作用是对CDK6的14倍。与palbociclib和ribociclib相比，abemaciclib对复合物CDK4/cyclin D1具有更高的选择性，IC50值比其他两种化合物低5倍[1]。

将细胞接种到 96 孔板中，然后让其粘附一整夜，然后用所示化合物或 DMSO 对照（0.1% v/v）处理 72 小时。按照制造商的指示，使用细胞计数试剂盒来评估细胞的活力和增殖。 CompuSyn用于分析mTOR抑制剂和Abemaciclib之间的关系。联合指数 (CI) 值为 1 表示相加药物相互作用，而 CI 值 <1 或 >1 表示协同或拮抗药物相互作用。

Absorption, Distribution and Excretion
The plasma concentration of the drug increases in a dose-proportional manner. Following a single oral dose administration of 200 mg abemaciclib, the mean peak plasma concentration (Cmax) of 158 ng/mL is reached after 6 hours. The median time to reach maximum plasma concentration (Tmax) ranges from 4-6 hours following an oral administration of abemaciclib over a range of 50–275 mg, but may range up to 24 hours. The absolute bioavailability of the drug is reported to be 45%.
Following a single oral dose of 150mg radiolabeled abemaciclib, approximately 81% of the total dose was recovered in feces while 3% of the dose was detected in urine. The majority of the drug is exceted as metabolites.
The geometric mean systemic volume of distribution is approximately 690.3 L (49% CV).
The geometric mean hepatic clearance (CL) of abemaciclib in patients was 26.0 L/h (51% CV).

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Metabolism / Metabolites
Abemaciclib mainly undergoes hepatic metabolism mediated by CYP3A4. The major metabolite formed is N-desethylabemaciclib (M2), while other metabolites hydroxyabemaciclib (M20), hydroxy-N-desethylabemaciclib (M18), and an oxidative metabolite (M1) are also formed. M2, M18, and M20 are equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma, respectively.

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Biological Half-Life
The mean plasma elimination half-life for abemaciclib in patients was 18.3 hours (72% CV).

Hepatotoxicity
In the large clinical trials, adverse events were common and led to dose reductions in up to one-half of patients and discontinuation in 9%. In preregistration clinical trials, ALT elevations occurred in 31% to 41% of abemaciclib treated subjects which were above 5 times the ULN in 3% to 5%. In one study, several recipients developed clinically apparent liver injury with jaundice and one recipient died of hepatic failure, but these outcomes were considered to be unrelated to abemaciclib therapy. Thus, there were no cases of clinically apparent liver injury that could be attributed to abemaciclib therapy during prelicensure studies. Since the approval and more widescale use of abemaciclib, there have been no published reports of its hepatotoxicity. Nevertheless, the high rate of serum enzyme elevations during therapy and the similarity of abemaciclib to ribociclib and palbociclib makes it an agent that should be suspected of causing rare instances of clinically significant liver injury.
Likelihood score: E* (unproved but suspected, rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of abemaciclib during breastfeeding. Because abemaciclib and its metabolites are over 90% bound to plasma proteins, the amount in milk is likely to be low. However, the manufacturer recommends that breastfeeding be discontinued during abemaciclib therapy and for 3 weeks after the final dose.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
According to in vitro models using animal brain tissues, the protein binding of abemaciclib is approximately 95-98%. While abemaciclib demonstrated *in vitro* binding to serum albumin, alpha-1-acid glycoprotein and other human plasma proteins in a concentration-depedent manner, its major metabolites are also shown to bind to plasms proteins as well. The approximate bound fractions of M2, M18 and M20 are 93.4%, 96.8% and 97.8%, respectively.

[1]. Drug Des Devel Ther . 2018 Feb 16:12:321-330.

[2]. Cancer Discov . 2016 Jul;6(7):740-53.

[3]. Cell Rep . 2018 Mar 13;22(11):2978-2994.

Abemaciclib is an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) that are involved in the cell cycle and promotion of cancer cell growth in case of unregulated activity. On September 28, 2017, FDA granted approval of abemaciclib treatment under the market name Verzenio for the treatment of HR-positive and HER2-negative advanced or metastatic breast cancer that has progressed after unsuccessful endocrine therapy. It is either given alone in patients who has undergone endocrine therapy and chemotherapy after the metastasis of cancer, or in combination with [DB00947]. Following oral treatment in patients with HR-positive, HER2-negative breast cancer, abemaciclib demonstrated increased progression-free survival rates and objective response rates. Abemaciclib has been used in trials studying the treatment of melanoma, lymphoma, neoplasm, solid tumor, and glioblastoma.
Abemaciclib is a Kinase Inhibitor. The mechanism of action of abemaciclib is as a Kinase Inhibitor.
Abemaciclib is a unique cyclin-dependent kinase inhibitor that is used in combination with an antiestrogen in the treatment of postmenopausal women with metastatic breast cancer. Abemaciclib is associated with a moderate rate of serum aminotransferase elevations during therapy and is suspected to be a rare cause of clinically apparent liver injury.
Abemaciclib is an orally available cyclin-dependent kinase (CDK) inhibitor that targets the CDK4 (cyclin D1) and CDK6 (cyclin D3) cell cycle pathway, with potential antineoplastic activity. Abemaciclib specifically inhibits CDK4 and 6, thereby inhibiting retinoblastoma (Rb) protein phosphorylation in early G1. Inhibition of Rb phosphorylation prevents CDK-mediated G1-S phase transition, thereby arresting the cell cycle in the G1 phase, suppressing DNA synthesis and inhibiting cancer cell growth. Overexpression of the serine/threonine kinases CDK4/6, as seen in certain types of cancer, causes cell cycle deregulation.
See also: Abemaciclib Mesylate (is active moiety of).

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Drug Indication
* Indicated in combination with fulvestrant for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. * Inidicated as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.
Early Breast CancerVerzenios in combination with endocrine therapy is indicated for the adjuvant treatment of adult patients with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative, node positive early breast cancer at high risk of recurrence (see section 5. 1). In pre or perimenopausal women, aromatase inhibitor endocrine therapy should be combined with a luteinising hormone-releasing hormone (LHRH) agonist. Advanced or Metastatic Breast CancerVerzenios is indicated for the treatment of women with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy, or in women who have received prior endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a LHRH agonist.
Treatment of glioma, Treatment of neuroblastoma
Treatment of Ewing sarcoma
Treatment of breast cancer

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Mechanism of Action
Regulation of cell cycle is crucial in maintaining proper cell growth; dysregulated cell cycle signalling pathway is a key component in inducing hyperproliferation of cells and tumor formation in various cancers. G1 to S phase cell cycle progression, or transition through the G1 restriction point (R), is promoted by the retinoblastoma tumor suppressor protein (Rb)-mediated pathway. Activation of Rb-mediated pathway requires the interaction of Cyclin-dependent kinases (CDK) 4 and 6 with D-type cyclins, which drives the formation of active CDK4/CDK6 and subsequent phosphorylation of Rb. Rb is a tumor suppressant protein that inhibits proliferation through binding to and suppressing the activity of the E2F family of transcription factors. However, phosphorylation of Rb relieves suppression of E2F to allow expression of genes required for passage through the restriction point. This leads to increased expression of downstream signalling molecules and activity of protein kinases that promote the cell cycle progression and initiation of DNA replication. Phosphorylation of Rb and other proteins by CDK4/6 additionally leads to transcription of genes involved in cell cycle-independent activities including signal transduction, DNA repair transcriptional control, and mRNA processing. Abemaciclib selectively inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells. Unlike other CDK inhibitors such as [DB09073] and [DB11730], abemaciclib exhibits greater selectivity for CDK4 compared to CDK6.

C27H32F2N8

506.59

506.271

C, 64.01; H, 6.37; F, 7.50; N, 22.12

1231929-97-7

Abemaciclib methanesulfonate;1231930-82-7;Abemaciclib-d8;2088650-53-5

46220502

White to off-white solid powder

1.3±0.1 g/cm3

689.3±65.0 °C at 760 mmHg

370.7±34.3 °C

0.0±2.2 mmHg at 25°C

1.656

2.74

75

1

9

7

37

723

0

CC1=NC2=C(F)C=C(C3=NC(NC4=NC=C(CN5CCN(CC)CC5)C=C4)=NC=C3F)C=C2N1C(C)C

UZWDCWONPYILKI-UHFFFAOYSA-N

InChI=1S/C27H32F2N8/c1-5-35-8-10-36(11-9-35)16-19-6-7-24(30-14-19)33-27-31-15-22(29)25(34-27)20-12-21(28)26-23(13-20)37(17(2)3)18(4)32-26/h6-7,12-15,17H,5,8-11,16H2,1-4H3,(H,30,31,33,34)

N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-amine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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

配方 1 中的溶解度: 3.33 mg/mL (6.57 mM) in 0.5% HEC (这些助溶剂从左到右依次添加，逐一添加), 悬浮液；超声助溶。

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配方 2 中的溶解度: 5% DMSO+40% PEG 300+5%Tween80+ 50%ddH2O: 0.2mg/ml

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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;
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7、 以上所有助溶剂都可在 Invivochem.cn网站购买。