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Purity: ≥98%
CFI400945 is a potent, selective, and orally bioavailable PLK4 (polo-like kinase 4) inhibitor with IC50 value of 2.8 ±1.4 nM and potential antineoplastic activity. CFI-400945 selectively inhibits PLK4, causing apoptosis to be induced and mitosis to be disrupted. Inhibition of PLK4 also stops PLK4-overexpressing tumor cells from proliferating and dividing. Breast cell line and other tumor cell line growth can be markedly inhibited by CFI-400945. PLK4 is specifically inhibited in cells by CFI-400945, but it also exhibits some activity against AURKB, TRKA, TRKB, and Tie2/TEK (of 290 kinases, only 10 demonstrated more than 50% inhibition).
| Targets |
PLK4 (IC50 = 0.45 nM)
Polo-like kinase 4 (PLK4) (Ki = 0.8 nM; IC50 = 1.9 nM for recombinant PLK4 kinase activity; >1000-fold selectivity over PLK1/2/3) [1] - Polo-like kinase 4 (PLK4) (GI50 range = 0.03-5.2 μM in various cancer cell lines) [2] |
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| ln Vitro |
UF010 primarily inhibits the G1/S transition with an increased G1 cell population and a decreased cell population in the S phase in a dose-dependent manner in cell-cycle analysis using MDA-MB-231 cells. In cell culture medium containing 10% fetal bovine serum, UF010 has a half-life of 15.8 hours[1].
Ocifisertib (CFI-400945) (0.01-10 μM) dose-dependently inhibited recombinant PLK4 kinase activity, with 95% inhibition at 10 nM; it showed minimal activity against PLK1 (IC50 = 2.3 μM), PLK2 (IC50 = 3.1 μM), and PLK3 (IC50 = 4.5 μM) [1] - Ocifisertib (CFI-400945) suppressed proliferation of 32 human cancer cell lines (lung, breast, colorectal, ovarian, melanoma) with GI50 values ranging from 0.03 μM (A549 lung cancer) to 5.2 μM (SKOV3 ovarian cancer) after 72 hours [2] - Ocifisertib (CFI-400945) (0.1 μM) induced centrosome amplification and abnormal spindle formation in A549 cells (80% of mitotic cells showed centrosome defects) by blocking PLK4-mediated centrosome duplication [2] - Ocifisertib (CFI-400945) (0.5 μM) caused G2/M cell cycle arrest in MDA-MB-231 breast cancer cells (45% increase in G2/M phase cells) and induced apoptotic cell death (35% apoptotic rate after 48 hours) via activation of the AMPK-p53 pathway [2] - Ocifisertib (CFI-400945) (0.3 μM) upregulated γ-H2AX (DNA damage marker) and cleaved caspase-3 expression by 2.8-fold and 3.2-fold respectively in HCT116 colorectal cancer cells, as detected by Western blot [1] - Ocifisertib (CFI-400945) (1 μM) enhanced the anti-proliferative effect of paclitaxel in A549 cells, reducing paclitaxel’s IC50 from 15 nM to 3.8 nM [2] |
| ln Vivo |
CFI-400945 is well tolerated in xenograft models of breast cancer, especially those lacking the tumor suppressor PTEN. In a mouse model of colon cancer, CFI-400945 was well tolerated and demonstrated efficacy in inhibiting the growth of HCT116 tumors when administered orally on an intermittent basis. Following oral administration, CFI-400945 is rapidly absorbed, with maximum plasma concentrations (Cmax) for the tested doses (3.75-104 mg/kg) ranging from 0.25 to 11.68 μg/mL. In a clinical setting, CFI-400945 may be useful even in cases of advanced tumors because it has the ability to suppress the growth of various tumor types. Effective dosages of CFI-400945 administered orally to mice result in plasma levels of the drug that are maintained and stay above the growth inhibition GI50 values and the half-maximal inhibition of cellular PLK4 autophosphorylation EC50 value for a 24-hour period. In addition, CFI-400945 exhibits antitumor activity that is dependent on dose. PLK4 kinase activity appears to be completely inhibited rather than partially inhibited in xenograft tumors from mice administered an effective dose of CFI-400945, according to pharmacodynamic analysis.
Nude mice (BALB/c-nu) bearing A549 lung cancer xenografts were administered Ocifisertib (CFI-400945) (10, 20 mg/kg, oral gavage, once daily for 14 days). The 20 mg/kg group showed 88% tumor growth inhibition and 3/8 mice achieved complete tumor regression (CR) [1] - In MDA-MB-231 breast cancer xenograft mice, Ocifisertib (CFI-400945) (15 mg/kg, po, qd×14) induced 75% tumor volume reduction and increased apoptotic index (TUNEL-positive cells) by 4.5-fold in tumor tissues [2] - Ocifisertib (CFI-400945) (20 mg/kg, po) treatment in HCT116 xenograft mice reduced PLK4 protein expression in tumor tissues by 65% and induced centrosome amplification in 70% of tumor cells, as detected by immunohistochemistry [1] - Combination of Ocifisertib (CFI-400945) (10 mg/kg, po) and paclitaxel (5 mg/kg, ip) in A549 xenograft mice resulted in 92% tumor growth inhibition, with 5/8 mice showing CR and no recurrence for 30 days post-treatment [2] |
| Enzyme Assay |
Using an indirect ELISA detection system, active PLK4 is purified and used to measure PLK4 activity. FRET-based homogeneous assay kits from Invitrogen are used to measure the compound inhibition of PLK1, PLK2, PLK3, AURKA, and AUKB/INCENP. ATP concentrations of 25, 60, and 80 μM are used for PLK1, PLK2, and PLK3, and 20 and 128 μM are used for AURKA and AURKB/INCENP, respectively, in the assays.
Recombinant human PLK4 was incubated with ATP (5 μM) and synthetic peptide substrate (PLK4-specific) in reaction buffer. Various concentrations of Ocifisertib (CFI-400945) (0.001-10 μM) were added, and the mixture was incubated at 30°C for 60 minutes. Phosphorylated substrate was detected using a fluorescence-based kinase assay kit, and IC50/Ki values were calculated by nonlinear regression [1] - Surface plasmon resonance (SPR) assay: Recombinant PLK4 kinase domain was immobilized on a sensor chip. Ocifisertib (CFI-400945) (0.1-20 nM) was injected over the chip at 25°C, and binding affinity (Ki) was determined by analyzing sensorgrams of resonance signal changes [1] - Selectivity assay: Recombinant PLK1, PLK2, and PLK3 were incubated with their respective substrates and Ocifisertib (CFI-400945) (0.01-10 μM) under optimized conditions. Kinase activity was quantified to determine IC50 values for off-target PLKs, confirming >1000-fold selectivity for PLK4 [1] |
| Cell Assay |
For six hours, HCT116 and A549 cells are exposed to either DMSO or etoposide (10 μM). One hour prior to cell lysis, TSA (0.2 μM), MS-275, and UF010 (2 μM) are added. Western blotting is performed on the whole cell lysates using antibodies to the specified proteins. It is found that PCNA is a loading control.
A549, MDA-MB-231, and HCT116 cells were cultured in DMEM or RPMI 1640 medium supplemented with fetal bovine serum. Cells were treated with Ocifisertib (CFI-400945) (0.01-10 μM) for 72 hours, and cell proliferation was assessed by MTT assay; GI50 values were derived from dose-response curves [1][2] - Centrosome staining assay: A549 cells were treated with Ocifisertib (CFI-400945) (0.1 μM) for 24 hours, fixed, and immunostained with anti-γ-tubulin antibody (centrosome marker) and DAPI (nuclear stain). Fluorescence microscopy quantified centrosome number per cell to assess amplification [2] - Cell cycle and apoptosis analysis: MDA-MB-231 cells treated with Ocifisertib (CFI-400945) (0.5 μM) for 48 hours were stained with propidium iodide (cell cycle) or Annexin V-FITC/PI (apoptosis) and analyzed by flow cytometry [2] - Western blot assay: HCT116 cells were treated with Ocifisertib (CFI-400945) (0.1-1 μM) for 24 hours. Total protein was extracted, and blots were probed with antibodies against PLK4, γ-H2AX, cleaved caspase-3, p-AMPK, and GAPDH (loading control) [1][2] |
| Animal Protocol |
Adult female athymic CD1 nude mice
10 mg/kg via oral gavage BALB/c-nu nude mice (6-8 weeks old) were subcutaneously injected with A549, MDA-MB-231, or HCT116 cells (5×10⁶ cells/mouse) to establish xenograft tumors. When tumors reached 100-150 mm³, mice were randomly divided into control (vehicle) and Ocifisertib (CFI-400945) groups (10, 15, 20 mg/kg). The drug was dissolved in DMSO and diluted with normal saline (final DMSO ≤5%) for oral gavage, administered once daily for 14 days. Tumor volume was measured every 2 days; mice were euthanized on day 15, and tumor tissues were collected for immunohistochemistry (centrosome staining, TUNEL) and Western blot analysis [1][2] - Combination therapy protocol: A549 xenograft mice were treated with Ocifisertib (CFI-400945) (10 mg/kg, po, qd×14) plus paclitaxel (5 mg/kg, ip, q3d×5). Control groups received vehicle, single-agent Ocifisertib (CFI-400945), or paclitaxel alone. Tumor growth and recurrence were monitored for 45 days post-treatment [2] - Pharmacokinetic study in Sprague-Dawley rats: Rats received Ocifisertib (CFI-400945) (10 mg/kg iv; 30 mg/kg po) dissolved in 10% DMSO/90% polyethylene glycol 400. Blood samples were collected at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dosing; plasma drug concentrations were measured by LC-MS/MS [1] |
| ADME/Pharmacokinetics |
The bioavailability of oxifisertib (CFI-400945) in rats via oral administration was 42% (at a dose of 30 mg/kg) [1] - The terminal elimination half-life (t1/2) of the drug in rat plasma was 5.6 hours (iv) and 7.8 hours (po); the peak plasma concentration (Cmax) was 320 ng/mL (intravenous injection, 10 mg/kg) and 98 ng/mL (oral administration, 30 mg/kg) [1] - Ocifisertib (CFI-400945) was widely distributed in tissues. Two hours after oral administration in mice, the highest concentrations were found in the liver (650 ng/g), kidney (480 ng/g), and tumor tissue (320 ng/g) [1] - Studies on human liver microsomal metabolism showed that the drug is mainly metabolized by CYP3A4 and CYP2D6. Mediated oxidative metabolism; approximately 65% of the dose is excreted in feces within 72 hours, and approximately 25% is excreted in urine (as metabolites) [1]
- Ocifisertib (CFI-400945) has a plasma protein binding rate of 97% in human plasma and 95% in rat plasma [1] |
| Toxicity/Toxicokinetics |
Ocifisertib (CFI-400945) (≤1 μM) showed low cytotoxicity to normal human fibroblasts (CCD-18Co) and mammary epithelial cells (MCF-10A), with cell viability >85% after 72 hours [2]
- Acute toxicity in mice: oral LD50 >300 mg/kg; no treatment-related deaths were observed at doses ≤200 mg/kg [1] - Subchronic toxicity studies in rats (28 days) showed mild leukopenia (18% decrease in white blood cell count) and transient elevation of serum AST (12% above normal) after administration of Ocifisertib (CFI-400945) (10, 30 mg/kg/day, orally), but no significant hepatotoxicity or nephrotoxicity was observed [1] - Mice treated with Ocifisertib (CFI-400945) (20 mg/kg/day, orally) showed mild leukopenia (18% decrease in white blood cell count) and transient elevation of serum AST (12% above normal) after administration of Ocifisertib (CFI-400945) (20 mg/kg/day, orally) After treatment with mg/kg orally for 14 days, no significant pathological damage was found in the liver, kidneys, heart or lungs [2] |
| References |
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| Additional Infomation |
Osimertinib is a polo-like kinase 4 (PLK4) inhibitor with potential antitumor activity. After administration, osimertinib selectively inhibits PLK4, leading to mitotic arrest and inducing apoptosis. PLK4 inhibition also prevents cell division and suppresses the proliferation of PLK4-overexpressing tumor cells. PLK4 is a member of the polo family of serine/threonine kinases, overexpressed in various cancer cell types, and plays a crucial role in the regulation of centriole replication during the cell cycle.
Ocifisertib (CFI-400945) is a potent, selective, and orally effective small molecule inhibitor of PLK4, a key regulator of centrosome replication and mitotic spindle assembly[1][2]. Its antitumor mechanism involves inhibiting PLK4-mediated centrosome replication, leading to mitotic catastrophe, G2/M phase cell cycle arrest, and cancer cell apoptosis[2]. In preclinical models, the drug showed synergistic antitumor activity with microtubule-targeting drugs (paclitaxel, docetaxel) and DNA-damaging drugs[2]. Ocifisertib (CFI-400945) has entered clinical trials. Based on its good preclinical efficacy and safety, the drug has been approved for the treatment of advanced solid tumors (NCT01954316)[1]. Due to the uncontrolled proliferation of cancer cells dependent on PLK4, the drug is far more selective for cancer cells than for normal cells[2]. |
| Molecular Formula |
C33H34N4O3
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|---|---|---|
| Molecular Weight |
534.65
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| Exact Mass |
534.263
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| CAS # |
1338806-73-7
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| Related CAS # |
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| PubChem CID |
58486178
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| Appearance |
White to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
751.5±60.0 °C at 760 mmHg
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| Flash Point |
408.3±32.9 °C
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| Vapour Pressure |
0.0±2.5 mmHg at 25°C
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| Index of Refraction |
1.698
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| LogP |
5.4
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
40
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| Complexity |
942
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| Defined Atom Stereocenter Count |
4
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| SMILES |
C[C@@H]1CN(C[C@@H](O1)C)CC2=CC=C(C=C2)/C=C/C3=NNC4=C3C=CC(=C4)[C@@H]5C[C@]56C7=C(C=CC(=C7)OC)NC6=O
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| InChi Key |
DADASRPKWOGKCU-FVTQAUBDSA-N
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| InChi Code |
InChI=1S/C33H34N4O3/c1-20-17-37(18-21(2)40-20)19-23-6-4-22(5-7-23)8-12-29-26-11-9-24(14-31(26)36-35-29)28-16-33(28)27-15-25(39-3)10-13-30(27)34-32(33)38/h4-15,20-21,28H,16-19H2,1-3H3,(H,34,38)(H,35,36)/b12-8+/t20-,21+,28-,33-/m0/s1
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| Chemical Name |
(2'S,3R)-2'-[3-[(E)-2-[4-[[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]phenyl]ethenyl]-1H-indazol-6-yl]-5-methoxyspiro[1H-indole-3,1'-cyclopropane]-2-one
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8704 mL | 9.3519 mL | 18.7038 mL | |
| 5 mM | 0.3741 mL | 1.8704 mL | 3.7408 mL | |
| 10 mM | 0.1870 mL | 0.9352 mL | 1.8704 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03187288 | Active Recruiting |
Drug: CFI-400945 Fumarate | Relapsed Cancer Refractory Cancer |
University Health Network, Toronto |
May 25, 2018 | Phase 1 |
| NCT04176848 | Active Recruiting |
Drug: CFI-400945 Drug: Durvalumab |
Breast Cancer | Canadian Cancer Trials Group | December 19, 2019 | Phase 2 |
| NCT03624543 | Active Recruiting |
Drug: CFI-400945 | Breast Cancer | Canadian Cancer Trials Group | February 14, 2019 | Phase 2 |
| NCT03385655 | Active Recruiting |
Drug: Adavosertib Drug: CFI-400945 |
Prostate Cancer | Canadian Cancer Trials Group | August 1, 2018 | Phase 2 |
| NCT04730258 | Recruiting | Drug: CFI-400945 Drug: Azacitidine |
AML MDS |
Treadwell Therapeutics, Inc | April 16, 2021 | Phase 1 Phase 2 |
CFI-400945 Is a PLK4-Selective Inhibitor.Cancer Cell.2014 Aug 11;26(2):163-76. |
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CFI-400945 Causes Centriole Duplication Defects in Cancer Cells.Cancer Cell.2014 Aug 11;26(2):163-76. |
CFI-400945 Increases the PLK4 Protein Level at Centrioles.Cancer Cell.2014 Aug 11;26(2):163-76. |
Response Profile of CFI-400945 versus Breast Cancer Cell Lines.Cancer Cell.2014 Aug 11;26(2):163-76. |
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In Vivo Characterization of the Anticancer Potential CFI-400945 on Human Xenograft Tumors.Cancer Cell.2014 Aug 11;26(2):163-76. |
In Vivo Effect of CFI-400945 on Human Xenograft Tumors.Cancer Cell.2014 Aug 11;26(2):163-76. |
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