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

Autor: David Blake, Peter Sheldrake, Chiara Saladino, Butrus Atrash, Sheelagh Frame, Edward McDonald, Craig MacKay, Paul A. Clarke, Daniella Zheleva, Paul Workman
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Adenosine
Kinase Inhibitors
Cancer Treatment
Apoptosis
Biochemistry
Hematologic Cancers and Related Disorders
Mice
chemistry.chemical_compound
hemic and lymphatic diseases
Breast Tumors
Medicine and Health Sciences
MCL1
Cell Cycle and Cell Division
Enzyme Inhibitors
Sulfonamides
Multidisciplinary
Cell Death
Myeloid leukemia
Hematology
Myeloid Leukemia
Cyclin-Dependent Kinases
Leukemia
Oncology
Cell Processes
Medicine
Refractory Chronic Lymphocytic Leukemia
Research Article
Acute Myeloid Leukemia
Science
Antineoplastic Agents
Biology
Cyclin-dependent kinase
Cyclins
Cell Line
Tumor
Leukemias
Breast Cancer
medicine
Animals
Humans
Protein Kinase Inhibitors
Seliciclib
Venetoclax
Cyclin-Dependent Kinase 2
Biology and Life Sciences
Cancers and Neoplasms
Correction
Cell Biology
Cell Cycle Checkpoints
Bridged Bicyclo Compounds
Heterocyclic
medicine.disease
Cyclin-Dependent Kinase 9
chemistry
Enzymology
Cancer research
biology.protein
Myeloid Cell Leukemia Sequence 1 Protein
CDK inhibitor
Zdroj: PLoS ONE, Vol 15, Iss 7, p e0234103 (2020)
PLoS ONE
ISSN: 1932-6203
Popis: 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).
Databáze: OpenAIRE
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