Fadraciclib free base | CYC065 | CAS#1070790-89-4 | CDK inhibitor

MedKoo Cat#: 206524 | Name: Fadraciclib free base

Description:

WARNING: This product is for research use only, not for human or veterinary use.

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

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: 397.2590

Molecular Weight: 397.53

Elemental Analysis: C, 63.45; H, 7.86; N, 24.66; O, 4.02

Price and Availability

Size	Price	Availability
10mg	USD 450.00	2 Weeks
25mg	USD 950.00	2 Weeks
50mg	USD 1,650.00	2 Weeks
100mg	USD 2,650.00	2 Weeks
200mg	USD 3,650.00	2 Weeks
500mg	USD 4,950.00	2 Weeks

Bulk Inquiry

Buy Now

Add to Cart

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; NSC806387; NSC 806387; NSC-806387; 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

More Info

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.

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#S8S02C27

QC Data

View QC data: current batch, Lot#S8S02C27

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

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.

	Solvent	mg/mL	mM
Solubility
	DMSO	100.0	251.55

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 397.53 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.

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:

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.

1: 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. 2: Chen R, Chen Y, Xiong P, Zheleva D, Blake D, Keating MJ, Wierda WG, Plunkett W. Cyclin-dependent kinase inhibitor fadraciclib (CYC065) depletes anti- apoptotic protein and synergizes with venetoclax in primary chronic lymphocytic leukemia cells. Leukemia. 2022 Jun;36(6):1596-1608. doi: 10.1038/s41375-022-01553-w. Epub 2022 Apr 5. PMID: 35383271; PMCID: PMC9162916. 3: PLOS ONE Staff. Correction: Fadraciclib (CYC065), a novel CDK inhibitor, targets key pro-survival and oncogenic pathways in cancer. PLoS One. 2021 May 6;16(5):e0251671. doi: 10.1371/journal.pone.0251671. Erratum for: PLoS One. 2020 Jul 9;15(7):e0234103. PMID: 33956908; PMCID: PMC8101907. 4: 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. 5: Chantkran W, Hsieh YC, Zheleva D, Frame S, Wheadon H, Copland M. Correction to: Interrogation of novel CDK2/9 inhibitor fadraciclib (CYC065) as a potential therapeutic approach for AML. Cell Death Discov. 2021 Jul 6;7(1):171. doi: 10.1038/s41420-021-00558-1. Erratum for: Cell Death Discov. 2021 Jun 10;7(1):137. PMID: 34230455; PMCID: PMC8260774. 6: Xiao L, Liu Y, Chen H, Shen L. Targeting CDK9 with selective inhibitors or degraders in tumor therapy: an overview of recent developments. Cancer Biol Ther. 2023 Dec 31;24(1):2219470. doi: 10.1080/15384047.2023.2219470. PMID: 37272701; PMCID: PMC10243401. 7: Poon E, Liang T, Jamin Y, Walz S, Kwok C, Hakkert A, Barker K, Urban Z, Thway K, Zeid R, Hallsworth A, Box G, Ebus ME, Licciardello MP, Sbirkov Y, Lazaro G, Calton E, Costa BM, Valenti M, De Haven Brandon A, Webber H, Tardif N, Almeida GS, Christova R, Boysen G, Richards MW, Barone G, Ford A, Bayliss R, Clarke PA, De Bono J, Gray NS, Blagg J, Robinson SP, Eccles SA, Zheleva D, Bradner JE, Molenaar J, Vivanco I, Eilers M, Workman P, Lin CY, Chesler L. Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma. J Clin Invest. 2020 Nov 2;130(11):5875-5892. doi: 10.1172/JCI134132. PMID: 33016930; PMCID: PMC7598076. 8: Aziz D, Portman N, Fernandez KJ, Lee C, Alexandrou S, Llop-Guevara A, Phan Z, Yong A, Wilkinson A, Sergio CM, Ferraro D, Etemadmoghadam D, Bowtell DD; kConFab Investigators; Serra V, Waring P, Lim E, Caldon CE. Synergistic targeting of BRCA1 mutated breast cancers with PARP and CDK2 inhibition. NPJ Breast Cancer. 2021 Aug 31;7(1):111. doi: 10.1038/s41523-021-00312-x. PMID: 34465787; PMCID: PMC8408175. 9: Decker JT, Kandagatla P, Wan L, Bernstein R, Ma JA, Shea LD, Jeruss JS. Cyclin E overexpression confers resistance to trastuzumab through noncanonical phosphorylation of SMAD3 in HER2+ breast cancer. Cancer Biol Ther. 2020 Nov 1;21(11):994-1004. doi: 10.1080/15384047.2020.1818518. Epub 2020 Oct 14. PMID: 33054513; PMCID: PMC7678934.