Interrogation of novel CDK2/9 inhibitor fadraciclib (CYC065) as a potential therapeutic approach for AML

Chantkran, Wittawat; Hsieh, Ya‐Ching; Zheleva, Daniella; Frame, Sheelagh; Wheadon, Helen; Copland, Mhairi

doi:10.1038/s41420-021-00496-y

Cited by 12 publications

(11 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The introduction of a substituent at the α position of the hydroxyl group at C-2 and the introduction of lutidine at C-6 to improve the water solubility of the molecule yielded the second-generation aminopurine CDK inhibitor fadraciclib (CYC065, 4 ). 4 can selectively act on CDK2 and 9. − In an ongoing clinical study investigating the use of 4 for the treatment of patients with advanced solid tumors, tumor shrinkage and stable disease (SD) have been observed in five patients with cyclin E-, MCL-1-, or myelocytomatosis- (Myc-)amplified advanced cancers . Compound 4 is currently in phase I clinical studies for the treatment of patients with advanced solid tumors (NCT02552953), and other clinical trials are investigating the combination of 4 and venetoclax for the treatment of patients with relapsed or refractory CLL (NCT03739554) and relapsed refractory AML or myelodysplastic syndrome (MDS, NCT04017546).…”

Section: Launched and Clinical Cdk Inhibitorsmentioning

confidence: 98%

From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer Therapy

et al. 2022

View full text Add to dashboard Cite

Herein, we discuss more than 50 cyclin-dependent kinase (CDK) inhibitors that have been approved or have undergone clinical trials and their therapeutic application in multiple cancers. This review discusses the design strategies, structure–activity relationships, and efficacy performances of these selective or nonselective CDK inhibitors. The theoretical basis of early broad-spectrum CDK inhibitors is similar to the scope of chemotherapy, but because their toxicity is greater than the benefit, there is no clinical therapeutic window. The notion that selective CDK inhibitors have a safer therapeutic potential than pan-CDK inhibitors has been widely recognized during the research process. Four CDK4/6 inhibitors have been approved for the treatment of breast cancer or for prophylactic administration during chemotherapy to protect bone marrow and immune system function. Furthermore, the emerging strategies in the field of CDK inhibitors are summarized briefly, and CDKs continue to be widely pursued as emerging anticancer drug targets for drug discovery.

show abstract

Section: Launched and Clinical Cdk Inhibitorsmentioning

confidence: 98%

From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer Therapy

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Addition of alvocidib to ICT improved response rates but not survival in a recently published phase 2 clinical trial [67] . Novel CDK9 inhibitors are currently in early phase trials [Table 2] [74][75][76][77][78] . BCL-XL inhibition by navitoclax has been shown to be active in preclinical AML models [79,80] .…”

Section: Apoptotic Inducersmentioning

confidence: 99%

Targeting regulated cell death pathways in acute myeloid leukemia

Garciaz¹,

Miller²,

Collette³

et al. 2023

Cancer Drug Resist

View full text Add to dashboard Cite

The use of the BCL2 inhibitor venetoclax has transformed the management of patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. By triggering intrinsic apoptosis, the drug is an excellent illustration of how our greater understanding of molecular cell death pathways can be translated into the clinic. Nevertheless, most venetoclax-treated patients will relapse, suggesting the need to target additional regulated cell death pathways. To highlight advances in this strategy, we review the recognized regulated cell death pathways, including apoptosis, necroptosis, ferroptosis and autophagy. Next, we detail the therapeutic opportunities to trigger regulated cell death in AML. Finally, we describe the main drug discovery challenges for regulated cell death inducers and their translation into clinical trials. A better knowledge of the molecular pathways regulating cell death represents a promising strategy to develop new drugs to cure resistant or refractory AML patients, particularly those resistant to intrinsic apoptosis.

show abstract

“…It exhibits improved potency and selectivity for CDK2 (IC 50 4.5 nM) and CDK9 (IC 50 26.2 nM) over the parental compound, as well as high selectivity across the kinome. In acute myeloid leukemia (AML), breast cancer cell lines and primary AML cells, fadraciclib has demonstrated actions that decreased RNA Pol II phosphorylation, reduced Mcl-1 level, and induced apoptosis [ 23 , 24 ]. The anti-cancer efficacy of fadraciclib has also been observed in vivo in AML xenograft models, in breast cancer models combined with trastuzumab [ 25 ] or eribulin [ 26 ], in uterine serous carcinoma models combined with taselisib or trastuzumab [ 27 ], as well as in MYCN-driven neuroblastoma [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

Cyclin-dependent kinase inhibitor fadraciclib (CYC065) depletes anti-apoptotic protein and synergizes with venetoclax in primary chronic lymphocytic leukemia cells

Chen

Xiong

et al. 2022

Leukemia

Self Cite

View full text Add to dashboard Cite

Fadraciclib (CYC065) is a second-generation aminopurine CDK2/9 inhibitor with increased potency and selectivity toward CDK2 and CDK9 compared to seliciclib (R-roscovitine). In chronic lymphocytic leukemia (CLL), a disease that depends on the over-expression of anti-apoptotic proteins for its survival, inhibition of CDK9 by fadraciclib reduced phosphorylation of the C-terminal domain of RNA polymerase II and blocked transcription in vitro; these actions depleted the intrinsically short-lived anti-apoptotic protein Mcl-1 and induced apoptosis. While the simulated bone marrow and lymph node microenvironments induced Mcl-1 expression and protected CLL cells from apoptosis, these conditions did not prolong the turnover rate of Mcl-1, and fadraciclib efficiently abrogated the protective effect. Further, fadraciclib was synergistic with the Bcl-2 antagonist venetoclax, inducing more profound CLL cell death, especially in samples with 17p deletion. While fadraciclib, venetoclax, and the combination each had distinct kinetics of cell death induction, their activities were reversible, as no additional cell death was induced upon removal of the drugs. The best combination effects were achieved when both drugs were maintained together. Altogether, this study provides a rationale for the clinical development of fadraciclib in CLL, either alone or in combination with a Bcl-2 antagonist.

show abstract

Interrogation of novel CDK2/9 inhibitor fadraciclib (CYC065) as a potential therapeutic approach for AML

Cited by 12 publications

References 72 publications

From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer Therapy

From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer Therapy

Targeting regulated cell death pathways in acute myeloid leukemia

Cyclin-dependent kinase inhibitor fadraciclib (CYC065) depletes anti-apoptotic protein and synergizes with venetoclax in primary chronic lymphocytic leukemia cells

Contact Info

Product

Resources

About