Physicochemical Properties
| Molecular Formula | C34H48N8O3 |
| Molecular Weight | 616.796727180481 |
| Exact Mass | 616.384 |
| CAS # | 1137212-79-3 |
| PubChem CID | 42640739 |
| Appearance | White to off-white solid powder |
| LogP | 3.6 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 9 |
| Rotatable Bond Count | 7 |
| Heavy Atom Count | 45 |
| Complexity | 1040 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | O=C1N(C2=CN=C(NC3C=CC(C(=O)N[C@H]4CC[C@H](N5CCN(C)CC5)CC4)=CC=3OC)N=C2N(C2CCCC2)CC21CC2)C |
| InChi Key | UFNLNMWVOMFWGS-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C34H48N8O3/c1-39-16-18-41(19-17-39)25-11-9-24(10-12-25)36-31(43)23-8-13-27(29(20-23)45-3)37-33-35-21-28-30(38-33)42(26-6-4-5-7-26)22-34(14-15-34)32(44)40(28)2/h8,13,20-21,24-26H,4-7,9-12,14-19,22H2,1-3H3,(H,36,43)(H,35,37,38) |
| Chemical Name | 4-[(9-cyclopentyl-5-methyl-6-oxospiro[8H-pyrimido[4,5-b][1,4]diazepine-7,1'-cyclopropane]-2-yl)amino]-3-methoxy-N-[4-(4-methylpiperazin-1-yl)cyclohexyl]benzamide |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | Plogosertib (CYC140) is >50-fold more powerful against PLK2 and PLK3 (IC50: 149 nM and 393 nM, respectively) and specifically inhibits PLK1 (IC50: 3 nM) [2]. The PLK1 substrate pSer4-nucleophosmin (p-NPM) is phosphorylated less in KYSE-410 cells when plogosertib (0–4 μM) is administered for two hours [2]. In HeLa cells, plogosertib (100 nM, 24 hours) increases the fraction of mitotic cells and unipolar spindles [2]. Plogosertib (72 h) is less harmful to non-malignant cell lines (IC50: 82 nM) and preferentially suppresses the growth of malignant cell lines (IC50: 14-21 nM) [2]. |
| ln Vivo | Preclinical xenograft models of acute leukemia and solid tumors show growth inhibition in response to Plogosertib (CYC140; oral, 40 mg/kg, 5/2/5 daily) [2]. The pharmacokinetic parameters of plogosertib (Compound A7, 1 mg/kg, mouse) are as follows: Cmax (453 ng/mL), AUC (377 hr·ng/mL), and Cl (2445 mL/h/kg)[3]. |
| Cell Assay |
Cell proliferation assay [2] Cell Types: KYSE-410 Cell Tested Concentrations: 0, 0.07, 0.15, 0.3, 0.6, 1.25 μM Incubation Duration: 72 h Experimental Results: Inhibition of cell proliferation in a concentration-dependent manner. Western Blot Analysis[2] Cell Types: KYSE-410 Cell Tested Concentrations: 0, 0.01, 0.025, 0.05, 0.1, 0.25, 0.5, 1, 2, 4 μM Incubation Duration: 2 hrs (hours) (p-NPM), 24 hrs (hours) (p -NPM) -HH3), 72 hrs (hours) (cPARP) Experimental Results: diminished phosphorylation of PLK1 substrate (p-NPM). Increased cleavage of mitotic markers pSer10 histone H3 (p-HH3) and PARP (cPARP, an indicator of cell death). |
| Animal Protocol |
Animal/Disease Models: HL60 promyelocytic leukemia xenograft [2] Doses: 40, 54, 67 mg/kg, 5/2/5 daily Route of Administration: Oral Experimental Results: Inhibition of tumor growth (>87%), and body weight Not Dramatically diminished. Animal/Disease Models: OE19 esophageal xenograft [2] Doses: 40 mg/kg, 5/2 daily Route of Administration: Oral Experimental Results:Inhibition of tumor growth (61% inhibition). |
| References |
[1]. Abstract 4178: The novel PLK1 inhibitor, CYC140: Identification of pharmacodynamic markers, sensitive target indications and potential combinations. Cancer Res (2017) 77 (13_Supplement): 4178. [2]. Therapeutic potential of novel PLK1 inhibitor CYC140 in esophageal cancer and acute leukemia. European Journal of Cancer, 2016, 1(69): S117. [3]. Treatment of proliferative diseases with pyrimidodiazepinones. Patent US20150320762A1. |
| Additional Infomation | Plogosertib is a competitive inhibitor for adenosine triphosphate (ATP) binding to polo-like kinase 1 (PLK1; PLK-1; STPK13), with potential antineoplastic activity. Upon administration, plogosertib selectively targets, binds to and inhibits PLK1, which disrupts mitosis and induces selective G2/M cell-cycle arrest followed by apoptosis in PLK1-overexpressing tumor cells. PLK1, named after the polo gene of Drosophila melanogaster, is a serine/threonine kinase that is crucial for the regulation of mitosis, and plays a key role in tumor cell proliferation, transformation and invasion. PLK1 expression is upregulated in a variety of tumor cell types and high expression is associated with increased aggressiveness and poor prognosis. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~100 mg/mL (~162.13 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.05 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.05 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (4.05 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6213 mL | 8.1064 mL | 16.2127 mL | |
| 5 mM | 0.3243 mL | 1.6213 mL | 3.2425 mL | |
| 10 mM | 0.1621 mL | 0.8106 mL | 1.6213 mL |