Fadraciclib free base
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MedKoo CAT#: 206524

CAS#: 1070790-89-4 (free base)

Description: Fadraciclib, also known as CYC065, is an orally bioavailable inhibitor of cyclin dependent kinases 2, 5 and 9 (CDK2/5/9) 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.


Chemical Structure

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Fadraciclib free base
CAS# 1070790-89-4 (free base)

Theoretical Analysis

MedKoo Cat#: 206524
Name: Fadraciclib free base
CAS#: 1070790-89-4 (free base)
Chemical Formula: C21H31N7O
Exact Mass: 397.259
Molecular Weight: 397.527
Elemental Analysis: C, 63.45; H, 7.86; N, 24.66; O, 4.02

Price and Availability

Size Price Availability Quantity
10.0mg USD 450.0 2 Weeks
25.0mg USD 950.0 2 Weeks
50.0mg USD 1650.0 2 Weeks
100.0mg USD 2650.0 2 Weeks
200.0mg USD 3650.0 2 Weeks
500.0mg USD 4950.0 2 Weeks
Bulk inquiry

Related CAS #: 1070790-89-4 (free base)   1315571-38-0 (HCl)   1315571-33-5 (tartrate)   1315571-34-6 (citrate)   1315571-36-8 (besylate)   1315571-40-4 (mesylate)    

Synonym: CYC065; CYC-065; CYC 065; Fadraciclib

IUPAC/Chemical Name: (2R,3S)-3-((6-(((4,6-dimethylpyridin-3-yl)methyl)amino)-9-isopropyl-9H-purin-2-yl)amino)pentan-2-ol

InChi Key: DLPIYBKBHMZCJI-WBVHZDCISA-N

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

SMILES Code: C[C@@H](O)[C@@H](NC1=NC(NCC2=C(C)C=C(C)N=C2)=C3N=CN(C(C)C)C3=N1)CC

Appearance: White to off-white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: CDK2 and CDK9
In vitro activity: In AML cell lines, myeloid cell leukemia 1 (MCL-1) was downregulated following treatment with fadraciclib, resulting in a rapid induction of apoptosis. In addition, RNA polymerase II (RNAPII)-driven transcription was suppressed, rendering a global gene suppression. Rapid induction of apoptosis was observed in primary AML cells after treatment with fadraciclib for 6-8 h. Twenty-four hours continuous treatment further increased efficacy of fadraciclib. Although preliminary results showed that AML cell lines harboring KMT2A rearrangement (KMT2A-r) are more sensitive to fadraciclib, we found that the drug can induce apoptosis and decrease MCL-1 expression in primary AML cells, regardless of KMT2A status. Importantly, the diversity of genetic mutations observed in primary AML patient samples was associated with variable response to fadraciclib, confirming the need for patient stratification to enable a more effective and personalized treatment approach. Synergistic activity was demonstrated when fadraciclib was combined with the BCL-2 inhibitor venetoclax, or the conventional chemotherapy agents, cytarabine, or azacitidine, with the combination of fadraciclib and azacitidine having the most favorable therapeutic window. In summary, these results highlight the potential of fadraciclib as a novel therapeutic approach for AML. Reference: Chantkran W, Hsieh YC, Zheleva D, Frame S, Wheadon H, Copland M. Interrogation of novel CDK2/9 inhibitor fadraciclib (CYC065) as a potential therapeutic approach for AML. Cell Death Discov. 2021 Jun 10;7(1):137. doi: 10.1038/s41420-021-00496-y. Erratum in: Cell Death Discov. 2021 Jul 6;7(1):171. PMID: 34112754; PMCID: PMC8192769.
In vivo activity: Studies of leukemia cell line sensitivity identify mixed lineage leukemia (MLL) gene status and the level of B-cell lymphoma 2 (BCL2) family proteins as potential markers for selection of patients with greater sensitivity to fadraciclib. We show that the combination of fadraciclib with BCL2 inhibitors, including venetoclax, is synergistic in leukemic cell models, as predicted from simultaneous inhibition of MCL1 and BCL2 pro-survival pathways. Fadraciclib preclinical pharmacology data support its therapeutic potential in CDK9- or CDK2-dependent cancers and as a rational combination with BCL2 inhibitors in hematological malignancies. Fadraciclib is currently in Phase 1 clinical studies in patients with advanced solid tumors (NCT02552953) and also in combination with venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) (NCT03739554) and relapsed refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (NCT04017546). Reference: Frame S, Saladino C, MacKay C, Atrash B, Sheldrake P, McDonald E, Clarke PA, Workman P, Blake D, Zheleva D. Fadraciclib (CYC065), a novel CDK inhibitor, targets key pro-survival and oncogenic pathways in cancer. PLoS One. 2020 Jul 9;15(7):e0234103. doi: 10.1371/journal.pone.0234103. Erratum in: PLoS One. 2021 May 6;16(5):e0251671. PMID: 32645016; PMCID: PMC7347136.

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 100.0 251.55

Preparing Stock Solutions

The following data is based on the product molecular weight 397.527 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: Chantkran W, Hsieh YC, Zheleva D, Frame S, Wheadon H, Copland M. Interrogation of novel CDK2/9 inhibitor fadraciclib (CYC065) as a potential therapeutic approach for AML. Cell Death Discov. 2021 Jun 10;7(1):137. doi: 10.1038/s41420-021-00496-y. Erratum in: Cell Death Discov. 2021 Jul 6;7(1):171. PMID: 34112754; PMCID: PMC8192769.
In vitro protocol: Chantkran W, Hsieh YC, Zheleva D, Frame S, Wheadon H, Copland M. Interrogation of novel CDK2/9 inhibitor fadraciclib (CYC065) as a potential therapeutic approach for AML. Cell Death Discov. 2021 Jun 10;7(1):137. doi: 10.1038/s41420-021-00496-y. Erratum in: Cell Death Discov. 2021 Jul 6;7(1):171. PMID: 34112754; PMCID: PMC8192769.
In vivo protocol: Frame S, Saladino C, MacKay C, Atrash B, Sheldrake P, McDonald E, Clarke PA, Workman P, Blake D, Zheleva D. Fadraciclib (CYC065), a novel CDK inhibitor, targets key pro-survival and oncogenic pathways in cancer. PLoS One. 2020 Jul 9;15(7):e0234103. doi: 10.1371/journal.pone.0234103. Erratum in: PLoS One. 2021 May 6;16(5):e0251671. PMID: 32645016; PMCID: PMC7347136.

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Note: structure was from Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy
Miniperspective
Yogesh A. Sonawane, Margaret A. Taylor, John Victor Napoleon, Sandeep Rana, Jacob I. Contreras,
and Amarnath Natarajan*



Additional Information

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.