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Fadraciclib (CYC-065) is a novel, 2nd generation, ATP-competitive and orally bioavailable inhibitor of cyclin dependent kinases 2, 5 and 9 (CDK2/5/9, IC50s of 5 and 26 nM for CDK2/9) with potential antineoplastic and chemoprotective activities. CYC065 selectively binds to and inhibits the activity of CDK2, 5 and 9, which leads to inhibition of CDK2, 5 and 9-dependent cellular pathways, downregulation of genes involved in the pro-survival pathway, prevention of the activation of DNA double-strand break repair pathways, and induction of both cell cycle arrest and apoptosis. This inhibits the proliferation of CDK2/5/9-overexpressing tumor cells. In addition, CYC065 protects hematopoietic stem and progenitor cells (HSPCs), prevents myelosuppression, and preserves the function of the bone marrow.
| ln Vitro |
Fadraciclib stops cells in the G1 phase of the cell cycle and reduces cell development, notably in uterine serous carcinoma (USC) overexpressing cyclin E1 (CCNE1). USC cell lines expressing high CCNE1 mRNA and protein levels were significantly more sensitive to in vitro Fadraciclib treatment compared to low CCNE1 expressing cell lines (IC50: mean ± sd = 124.1 ± in CCNE1 overexpressing USC cell lines vs. 415 cell lines 57.8 nM) and ±117.5 nM respectively in CCNE1 low-expression proteins; P=0.0003). Importantly, modest dosages of Fadraciclib (i.e., 100 nM) cause cell cycle G1 phase arrest only in CCNE1-overexpressing USC cell lines (i.e., USC-ARK-2, USC-ARK-7) [1].
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| ln Vivo |
USC-ARK-2-derived xenografts were treated with Fadraciclib (22.5 mg/kg) daily for three weeks in order to assess the therapeutic potential of the drug as a stand-alone treatment. Twice a week, the growth of the tumor and the weight of the mice were noted. When compared to mice treated with a vehicle, daily dose of Fadraciclib significantly slowed the growth of the tumor (beginning on day 9 of therapy, P=0.012). Throughout the whole course of the medication, no discernible weight reduction was noted [1].
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| References | |
| Additional Infomation |
CYC-065 is under investigation in clinical trial NCT03739554 (CYC065 CDK Inhibitor and Venetoclax Study in Relapsed/Refractory CLL).
Fadraciclib is an orally bioavailable inhibitor of cyclin dependent kinases 2, 5 and 9 (CDK2/5/9), with potential antineoplastic and chemoprotective activities. Upon oral administration, fadraciclib selectively binds to and inhibits the activity of CDK2, 5 and 9, which leads to inhibition of CDK2, 5 and 9-dependent cellular pathways, downregulation of genes involved in the pro-survival pathway, prevention of the activation of DNA double-strand break repair pathways, and induction of both cell cycle arrest and apoptosis. This inhibits the proliferation of CDK2/5/9-overexpressing tumor cells. In addition, CYC065 protects hematopoietic stem and progenitor cells (HSPCs), prevents myelosuppression, and preserves the function of the bone marrow. CDKs are serine/threonine kinases involved in the regulation of the cell cycle and may be overexpressed in certain cancer cell types; they play key roles in tumor cell proliferation, the regulation of transcription, and DNA damage repair. |
| Molecular Formula |
C21H31N7O
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|---|---|
| Molecular Weight |
397.51714348793
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| CAS # |
1070790-89-4
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| Related CAS # |
1070790-89-4;1315571-38-0 (HCl);1315571-33-5 (tartrate);1315571-34-6 (citrate); 1315571-36-8 (besylate); 1315571-40-4 (mesylate);
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| PubChem CID |
24983461
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
29
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| Complexity |
507
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| Defined Atom Stereocenter Count |
2
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| SMILES |
O[C@H](C)[C@H](CC)NC1=NC(=C2C(=N1)N(C=N2)C(C)C)NCC1C=NC(C)=CC=1C
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| InChi Key |
DLPIYBKBHMZCJI-WBVHZDCISA-N
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| InChi Code |
InChI=1S/C21H31N7O/c1-7-17(15(6)29)25-21-26-19(18-20(27-21)28(11-24-18)12(2)3)23-10-16-9-22-14(5)8-13(16)4/h8-9,11-12,15,17,29H,7,10H2,1-6H3,(H2,23,25,26,27)/t15-,17+/m1/s1
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| Chemical Name |
(2R,3S)-3-((6-(((4,6-dimethylpyridin-3-yl)methyl)amino)-9-isopropyl-9H-purin-2-yl)amino)pentan-2-ol
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| Synonyms |
CYC065 CYC-065 CYC 065
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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 |
| 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) |
DMSO : ≥ 100 mg/mL (~251.56 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.29 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 (6.29 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.29 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.5 mg/mL (6.29 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5156 mL | 12.5780 mL | 25.1560 mL | |
| 5 mM | 0.5031 mL | 2.5156 mL | 5.0312 mL | |
| 10 mM | 0.2516 mL | 1.2578 mL | 2.5156 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.
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