Reference Detail

Ref Type

Journal Article

PMID

(32645016)

Authors

Frame S, Saladino C, MacKay C, Atrash B, Sheldrake P, McDonald E, Clarke PA, Workman P, Blake D, Zheleva D

Title

Fadraciclib (CYC065), a novel CDK inhibitor, targets key pro-survival and oncogenic pathways in cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
PloS one	15	7	2020	e0234103	PLoS One

URL

Abstract Text

Cyclin-dependent kinases (CDKs) contribute to the cancer hallmarks of uncontrolled proliferation and increased survival. As a result, over the last two decades substantial efforts have been directed towards identification and development of pharmaceutical CDK inhibitors. Insights into the biological consequences of CDK inhibition in specific tumor types have led to the successful development of CDK4/6 inhibitors as treatments for certain types of breast cancer. More recently, a new generation of pharmaceutical inhibitors of CDK enzymes that regulate the transcription of key oncogenic and pro-survival proteins, including CDK9, have entered clinical development. Here, we provide the first disclosure of the chemical structure of fadraciclib (CYC065), a CDK inhibitor and clinical candidate designed by further optimization from the aminopurine scaffold of seliciclib. We describe its synthesis and mechanistic characterization. Fadraciclib exhibits improved potency and selectivity for CDK2 and CDK9 compared to seliciclib, and also displays high selectivity across the kinome. We show that the mechanism of action of fadraciclib is consistent with potent inhibition of CDK9-mediated transcription, decreasing levels of RNA polymerase II C-terminal domain serine 2 phosphorylation, the pro-survival protein Myeloid Cell Leukemia 1 (MCL1) and MYC oncoprotein, and inducing rapid apoptosis in cancer cells. This cellular potency and mechanism of action translate to promising anti-cancer activity in human leukemia mouse xenograft models. 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).

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
CYC065	CYC065	2	3

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
CYC065		Fadraciclib\|CYC-065\|CYC 065	CDK2 Inhibitor 31 CDK5 Inhibitor 8 CDK9 Inhibitor 21	CYC065 (Fadraciclib) inhibits CDK2, CDK5, and CDK9, potentially resulting in decreased tumor cell growth (PMID: 28376145, PMID: 27351214, PMID: 32645016).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KMT2A rearrange	acute myeloid leukemia	sensitive	CYC065	Preclinical - Cell line xenograft	Actionable	In a preclinical study, CYC065 (Fadraciclib) treatment resulted in decreased cell viability in an acute myeloid leukemia cell line harboring a KMT2A rearrangement in culture and inhibited tumor growth in a cell line xenograft model (PMID: 32645016).	32645016
KMT2A rearrange	acute lymphoblastic leukemia	predicted - sensitive	CYC065	Preclinical - Cell culture	Actionable	In a preclinical study, acute lymphoblastic leukemia cell lines harboring KMT2A rearrangements were sensitive to treatment with CYC065 (Fadraciclib) in culture (PMID: 32645016).	32645016