Characterization of a Dual CDC7/CDK9 Inhibitor in Multiple Myeloma Cellular Models

Natoni, Alessandro; Coyne, M.; Jacobsen, Alan J.; Rainey, Michael D.; O'Brien, Gemma; Healy, Sandra; Montagnoli, Alessia; Moll, Jürgen; O’Dwyer, Michael; Santocanale, Corrado

doi:10.3390/cancers5030901

Cited by 18 publications

(11 citation statements)

References 48 publications

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“…Hence PHA-767491 is a dual DDK/Cdk9 inhibitor. Recent studies have suggested that inhibition of Cdk9, a kinase that targets RNA Polymerase II, might enhance the apoptotic response induced by PHA-767491 in some cell lines [43] – [45] . Modifications of this compound led to the identification of several other potent inhibitors of DDK with some exhibiting superior selectivity and sensitivity [46] – [48] .…”

Section: Introductionmentioning

confidence: 99%

The Potent Cdc7-Dbf4 (DDK) Kinase Inhibitor XL413 Has Limited Activity in Many Cancer Cell Lines and Discovery of Potential New DDK Inhibitor Scaffolds

Sasi

Tiwari

Soon³

et al. 2014

PLoS ONE

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Cdc7-Dbf4 kinase or DDK (Dbf4-dependent kinase) is required to initiate DNA replication by phosphorylating and activating the replicative Mcm2-7 DNA helicase. DDK is overexpressed in many tumor cells and is an emerging chemotherapeutic target since DDK inhibition causes apoptosis of diverse cancer cell types but not of normal cells. PHA-767491 and XL413 are among a number of potent DDK inhibitors with low nanomolar IC50 values against the purified kinase. Although XL413 is highly selective for DDK, its activity has not been extensively characterized on cell lines. We measured anti-proliferative and apoptotic effects of XL413 on a panel of tumor cell lines compared to PHA-767491, whose activity is well characterized. Both compounds were effective biochemical DDK inhibitors but surprisingly, their activities in cell lines were highly divergent. Unlike PHA-767491, XL413 had significant anti-proliferative activity against only one of the ten cell lines tested. Since XL413 did not effectively inhibit DDK in multiple cell lines, this compound likely has limited bioavailability. To identify potential leads for additional DDK inhibitors, we also tested the cross-reactivity of ∼400 known kinase inhibitors against DDK using a DDK thermal stability shift assay (TSA). We identified 11 compounds that significantly stabilized DDK. Several inhibited DDK with comparable potency to PHA-767491, including Chk1 and PKR kinase inhibitors, but had divergent chemical scaffolds from known DDK inhibitors. Taken together, these data show that several well-known kinase inhibitors cross-react with DDK and also highlight the opportunity to design additional specific, biologically active DDK inhibitors for use as chemotherapeutic agents.

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Section: Introductionmentioning

confidence: 99%

The Potent Cdc7-Dbf4 (DDK) Kinase Inhibitor XL413 Has Limited Activity in Many Cancer Cell Lines and Discovery of Potential New DDK Inhibitor Scaffolds

Sasi

Tiwari

Soon³

et al. 2014

PLoS ONE

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“…Major pharmaceutical companies such as Bayer (BAY1143572/ Atuveciclib), Pfizer (PHA-767491), Eli Lilly (LY2857785), and AstraZeneca (AZ5576) have developed their own CDK9 inhibitors which are being tested in pre-clinical and clinical studies of many disease models including B-or T-Cell Leukemia/Lymphoma, esophageal adenocarcinoma, acute myelogenous leukemia, primary peritoneal carcinoma, chronic lymphocytic leukemia, relapsed multiple myeloma, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, acute biphenotypic leukemias, advanced breast cancer, non-small cell lung cancer, solid advanced tumors, etc. [244][245][246][247][248][249]. Including Alvocidib, there are several CDK9 inhibitors including Dinaciclib, Seliciclib, Atuveciclib, Voruciclib, and SNS-032, which are being examined in clinical trials for treatments of these diseases [250][251][252][253] (Table 3).…”

Section: Suppressing P-tefb Activitymentioning

confidence: 99%

P-TEFb as A Promising Therapeutic Target

Fujinaga

2020

Molecules

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The positive transcription elongation factor b (P-TEFb) was first identified as a general factor that stimulates transcription elongation by RNA polymerase II (RNAPII), but soon afterwards it turned out to be an essential cellular co-factor of human immunodeficiency virus (HIV) transcription mediated by viral Tat proteins. Studies on the mechanisms of Tat-dependent HIV transcription have led to radical advances in our knowledge regarding the mechanism of eukaryotic transcription, including the discoveries that P-TEFb-mediated elongation control of cellular transcription is a main regulatory step of gene expression in eukaryotes, and deregulation of P-TEFb activity plays critical roles in many human diseases and conditions in addition to HIV/AIDS. P-TEFb is now recognized as an attractive and promising therapeutic target for inflammation/autoimmune diseases, cardiac hypertrophy, cancer, infectious diseases, etc. In this review article, I will summarize our knowledge about basic P-TEFb functions, the regulatory mechanism of P-TEFb-dependent transcription, P-TEFb’s involvement in biological processes and diseases, and current approaches to manipulating P-TEFb functions for the treatment of these diseases.

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“…However, only two reports have appeared in the literature concerning CDC7 inhibition in myeloma cells. In one, PHA-767491, an inhibitor of both CDC7 and CDK9, demonstrated anti-myeloma activity both in cells obtained from patients and in cell cultures [ 152 ]. Another compound, the related pyrrolopyridinone (designated 89S), inhibited two myeloma cell lines at low micromolar concentrations [ 153 ].…”

Section: Cell Cycle Control S/tkmentioning

confidence: 99%

Kinase inhibitors as potential agents in the treatment of multiple myeloma

Abramson

2016

Oncotarget

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Recent years have witnessed a dramatic increase in the number of therapeutic options available for the treatment of multiple myeloma (MM) - from immunomodulating agents to proteasome inhibitors to histone deacetylase (HDAC) inhibitors and, most recently, monoclonal antibodies. Used in conjunction with autologous hematopoietic stem cell transplantation, these modalities have nearly doubled the disease's five-year survival rate over the last three decades to about 50%. In spite of these advances, MM still is considered incurable as resistance and relapse are common. While small molecule protein kinase inhibitors have made inroads in the therapy of a number of cancers, to date their application to MM has been less than successful. Focusing on MM, this review examines the roles played by a number of kinases in driving the malignant state and the rationale for target development in the design of a number of kinase inhibitors that have demonstrated anti-myeloma activity in both in vitro and in vivo xenograph models, as well as those that have entered clinical trials. Among the targets and their inhibitors examined are receptor and non-receptor tyrosine kinases, cell cycle control kinases, the PI3K/AKT/mTOR pathway kinases, protein kinase C, mitogen-activated protein kinase, glycogen synthase kinase, casein kinase, integrin-linked kinase, sphingosine kinase, and kinases involved in the unfolded protein response.

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Characterization of a Dual CDC7/CDK9 Inhibitor in Multiple Myeloma Cellular Models

Cited by 18 publications

References 48 publications

The Potent Cdc7-Dbf4 (DDK) Kinase Inhibitor XL413 Has Limited Activity in Many Cancer Cell Lines and Discovery of Potential New DDK Inhibitor Scaffolds

The Potent Cdc7-Dbf4 (DDK) Kinase Inhibitor XL413 Has Limited Activity in Many Cancer Cell Lines and Discovery of Potential New DDK Inhibitor Scaffolds

P-TEFb as A Promising Therapeutic Target

Kinase inhibitors as potential agents in the treatment of multiple myeloma

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