PF-06873600
(Synonyms: PF-3600) 目录号 : GC32832
An inhibitor of Cdk2, Cdk4, and Cdk6
Cas No.:2185857-97-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
PF-06873600 is an inhibitor of cyclin-dependent kinase 2 (Cdk2), Cdk4, and Cdk6 (Kis = 0.13, 1.25, and 0.11 nM, respectively).1 It is selective for these CDKs over Cdk1 and Cdk9 (Kis = 4.5 and 19.6 nM, respectively). PF-06873600 inhibits the phosphorylation of RB transcriptional corepressor 1 (RB1) in, and the proliferation of, OVCAR-3 ovarian cancer cells (EC50s = 19 and 45 nM, respectively). In vivo, PF-06873600 (30 mg/kg) reduces tumor volume in CTG-0464 and CTG-01912 non-small cell lung cancer (NSCLC) patient-derived xenograft (PDX) mouse models.
1.Freeman-Cook, K.D., Hoffman, R.L., Behenna, D.C., et al.Discovery of PF-06873600, a CDK2/4/6 inhibitor for the treatment of cancerJ. Med. Chem.64(13)9056-9077(2021)
| Cas No. | 2185857-97-8 | SDF | |
| 别名 | PF-3600 | ||
| Canonical SMILES | O=S(N1CCC(NC2=NC3=C(C=C(C(F)F)C(N3[C@@H]4CCC[C@]4(O)C)=O)C=N2)CC1)(C)=O | ||
| 分子式 | C20H27F2N5O4S | 分子量 | 471.52 |
| 溶解度 | DMSO : 83.33 mg/mL (176.73 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1208 mL | 10.604 mL | 21.208 mL |
| 5 mM | 0.4242 mL | 2.1208 mL | 4.2416 mL |
| 10 mM | 0.2121 mL | 1.0604 mL | 2.1208 mL |
| 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） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 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，
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 saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Discovery of PF-06873600, a CDK2/4/6 Inhibitor for the Treatment of Cancer
J Med Chem 2021 Jul 8;64(13):9056-9077.PMID:34110834DOI:10.1021/acs.jmedchem.1c00159.
Control of the cell cycle through selective pharmacological inhibition of CDK4/6 has proven beneficial in the treatment of breast cancer. Extending this level of control to additional cell cycle CDK isoforms represents an opportunity to expand to additional tumor types and potentially provide benefits to patients that develop tumors resistant to selective CDK4/6 inhibitors. However, broad-spectrum CDK inhibitors have a long history of failure due to safety concerns. In this approach, we describe the use of structure-based drug design and Free-Wilson analysis to optimize a series of CDK2/4/6 inhibitors. Further, we detail the use of molecular dynamics simulations to provide insights into the basis for selectivity against CDK9. Based on overall potency, selectivity, and ADME profile, PF-06873600 (22) was identified as a candidate for the treatment of cancer and advanced to phase 1 clinical trials.
Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor
Cancer Cell 2021 Oct 11;39(10):1404-1421.e11.PMID:34520734DOI:10.1016/j.ccell.2021.08.009.
The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival in HR+/HER2- breast cancer when combined with anti-hormonals. We sought to discover PAL resistance mechanisms in preclinical models and through analysis of clinical transcriptome specimens, which coalesced on induction of MYC oncogene and Cyclin E/CDK2 activity. We propose that targeting the G1 kinases CDK2, CDK4, and CDK6 with a small-molecule overcomes resistance to CDK4/6 inhibition. We describe the pharmacodynamics and efficacy of PF-06873600 (PF3600), a pyridopyrimidine with potent inhibition of CDK2/4/6 activity and efficacy in multiple in vivo tumor models. Together with the clinical analysis, MYC activity predicts (PF3600) efficacy across multiple cell lineages. Finally, we find that CDK2/4/6 inhibition does not compromise tumor-specific immune checkpoint blockade responses in syngeneic models. We anticipate that (PF3600), currently in phase 1 clinical trials, offers a therapeutic option to cancer patients in whom CDK4/6 inhibition is insufficient to alter disease progression.
Restoring order at the cell cycle border: Co-targeting CDK4/6 and CDK2
Cancer Cell 2021 Oct 11;39(10):1302-1305.PMID:34506738DOI:10.1016/j.ccell.2021.08.007.
Overcoming resistance to CDK4/6 inhibitors is a major clinical challenge. In this issue of Cancer Cell, Freeman-Cook et al. study mechanisms of resistance to CDK4/6 inhibitors by employing a CRISPRa screen. They identify the cyclin E-CDK2 axis and Myc signaling as key pathways of resistance and develop PF-06873600, a selective CDK2/4/6 inhibitor.