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 |
Externí odkaz: | |
Nepřihlášeným uživatelům se plný text nezobrazuje | K zobrazení výsledku je třeba se přihlásit. |