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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 PloS one
Vol 15
Issue 7
Date 2020
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
Drug Name Trade Name Synonyms Drug Classes Drug Description
CYC065 Fadraciclib|CYC-065|CYC 065 CDK2 Inhibitor 23 CDK5 Inhibitor 8 CDK9 Inhibitor 19 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 - AFDN acute myeloid leukemia predicted - sensitive CYC065 Preclinical - Cell culture Actionable In a preclinical study, an acute myeloid leukemia cell line harboring KMT2A-AFDN was sensitive to treatment with CYC065 (Fadraciclib) in culture, demonstrating decreased cell viability (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
KMT2A - AFF1 FLT3 exon 14 ins acute myeloid leukemia predicted - sensitive CYC065 Preclinical - Cell culture Actionable In a preclinical study, an acute myeloid leukemia cell line harboring KMT2A-AFF1 and a FLT3-ITD was sensitive to treatment with CYC065 (Fadraciclib) in culture, demonstrating decreased cell viability (PMID: 32645016). 32645016
KMT2A - MLLT3 FLT3 exon 14 ins acute myeloid leukemia sensitive CYC065 Preclinical - Cell culture Actionable In a preclinical study, an acute myeloid leukemia cell line harboring a FLT3-ITD and KMT2A-MLLT3 was sensitive to treatment with CYC065 (Fadraciclib) in culture, demonstrating reduced cell viability, increased PARP cleavage, and decreased Mcl1 protein levels (PMID: 32645016). 32645016
KMT2A - MLLT3 acute myeloid leukemia predicted - sensitive CYC065 Preclinical - Cell culture Actionable In a preclinical study, an acute myeloid leukemia cell line harboring KMT2A-MLLT3 was sensitive to treatment with CYC065 (Fadraciclib) in culture (PMID: 32645016). 32645016