Simultaneous cotargeting of ATR and RNA Polymerase I transcription demonstrates synergistic antileukemic effects on acute myeloid leukemia

Wang, Tingting; Shatara, Margaret; Liu, Fangbing; Knight, Tristan; Edwards, Holly; Wang, Guan; Lin, Hai; Wang, Yue; Taub, Jeffrey W.

doi:10.1038/s41392-019-0076-3

Cited by 4 publications

(5 citation statements)

References 8 publications

(7 reference statements)

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“…RNA polymerase I (Pol I) has been shown to have greater transcriptional activity in AML cells as compared to normal myeloid precursors ( 42 ). Inhibition of Pol I promotes G2/M arrest by activating the ATR checkpoint, implying that ATR inhibitors would be appropriate combinatorial candidates ( 42 ). Indeed, AZD6738 was shown to be synergistic with Pol I inhibitor, CX5461, in AML cell lines and primary AML samples ( 42 ).…”

Section: Pre-clinical Data For Ddr Inhibitors In Hematological Cancersmentioning

confidence: 99%

“…Inhibition of Pol I promotes G2/M arrest by activating the ATR checkpoint, implying that ATR inhibitors would be appropriate combinatorial candidates ( 42 ). Indeed, AZD6738 was shown to be synergistic with Pol I inhibitor, CX5461, in AML cell lines and primary AML samples ( 42 ). Finally, the combination of WEE1 inhibition (using AZD1775 (AstraZeneca)) with ATR inhibition (using VE-822) in AML cell lines led to apoptosis via disruption of the G2/M checkpoint and increased replication stress ( 43 ).…”

Section: Pre-clinical Data For Ddr Inhibitors In Hematological Cancersmentioning

confidence: 99%

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Targeting the DNA damage response in hematological malignancies

De Mel,

Lee,

Tan

et al. 2024

Front. Oncol.

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Deregulation of the DNA damage response (DDR) plays a critical role in the pathogenesis and progression of many cancers. The dependency of certain cancers on DDR pathways has enabled exploitation of such through synthetically lethal relationships e.g., Poly ADP-Ribose Polymerase (PARP) inhibitors for BRCA deficient ovarian cancers. Though lagging behind that of solid cancers, DDR inhibitors (DDRi) are being clinically developed for haematological cancers. Furthermore, a high proliferative index characterize many such cancers, suggesting a rationale for combinatorial strategies targeting DDR and replicative stress. In this review, we summarize pre-clinical and clinical data on DDR inhibition in haematological malignancies and highlight distinct haematological cancer subtypes with activity of DDR agents as single agents or in combination with chemotherapeutics and targeted agents. We aim to provide a framework to guide the design of future clinical trials involving haematological cancers for this important class of drugs.

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Section: Pre-clinical Data For Ddr Inhibitors In Hematological Cancersmentioning

confidence: 99%

Section: Pre-clinical Data For Ddr Inhibitors In Hematological Cancersmentioning

confidence: 99%

Targeting the DNA damage response in hematological malignancies

De Mel,

Lee,

Tan

et al. 2024

Front. Oncol.

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“…It induces cell apoptosis partially through intrinsic apoptotic pathway and is independent of TP53 status. Taub et al reported that the combination of POL I inhibitor clinical candidate CX-5461 and ceralasertib synergistically inhibited the cell proliferation in AML cell lines CTS and U937 [48]. The addition of ceralasertib causes abolishment of the G2/M cell cycle checkpoint arrest, leading to better and synergistic anticancer effects.…”

Section: Rna Polymerase I (Pol I) Inhibitorsmentioning

confidence: 99%

Recent Advances in Synergistic Antitumor Effects Exploited from the Inhibition of Ataxia Telangiectasia and RAD3-Related Protein Kinase (ATR)

et al. 2022

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As one of the key phosphatidylinositol 3-kinase-related kinases (PIKKs) family members, ataxia telangiectasia and RAD3-related protein kinase (ATR) is crucial in maintaining mammalian cell genomic integrity in DNA damage response (DDR) and repair pathways. Dysregulation of ATR has been found across different cancer types. In recent years, the inhibition of ATR has been proven to be effective in cancer therapy in preclinical and clinical studies. Importantly, tumor-specific alterations such as ATM loss and Cyclin E1 (CCNE1) amplification are more sensitive to ATR inhibition and are being exploited in synthetic lethality (SL) strategy. Besides SL, synergistic anticancer effects involving ATRi have been reported in an increasing number in recent years. This review focuses on the recent advances in different forms of synergistic antitumor effects, summarizes the pharmacological benefits and ongoing clinical trials behind the biological mechanism, and provides perspectives for future challenges and opportunities. The hope is to draw awareness to the community that targeting ATR should have great potential in developing effective anticancer medicines.

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“…These properties are extremely advantageous for cancer therapeutics, and evident from recent work, CX-5461 is a promising therapeutic agent for a variety of targets. In fact, as research expands, so do the number of potential targets for CX-5461, including solid tumors, acute myeloid leukemia, , multiple myeloma, , neuroblastoma tumors, prostate cancer, osteosarcoma, acute lymphoblastic leukemia, , epithelial ovarian cancer, − arterial injury-induced neointimal hyperplasia, and even noncancerous diseases such as cytomegalovirus, , Herpes simplex type I virus, and African trypanosomiasis . However, without an experimentally solved structure of CX-5461 in complex with any G4 structure, the specific interactions associated with the binding of CX-5461 and ultimate stabilization of the G4 remain to be fully understood.…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Study on the Binding of an Anticancer DNA G-Quadruplex Stabilizer, CX-5461, to Human Telomeric, c-KIT1, and c-Myc G-Quadruplexes and a DNA Duplex

Sullivan

Chen

2020

J. Chem. Inf. Model.

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DNA G-quadruplex (G4) stabilizer, CX-5461, is in phase I/II clinical trials for advanced cancers with BRCA1/2 deficiencies. A FRET-melting temperature increase assay measured the stabilizing effects of CX-5461 to a DNA duplex (∼10 K), and three G4 forming sequences negatively implicated in the cancers upon its binding: human telomeric (∼30 K), c-KIT1 (∼27 K), and c-Myc (∼25 K). Without experimentally solved structures of these CX-5461–G4 complexes, CX-5461’s interactions remain elusive. In this study, we performed a total of 73.5 μs free ligand molecular dynamics binding simulations of CX-5461 to the DNA duplex and three G4s. Three binding modes (top, bottom, and side) were identified for each system and their thermodynamic, kinetic, and structural nature were deciphered. The molecular mechanics/Poisson Boltzmann surface area binding energies of CX-5461 were calculated for the human telomeric (−28.6 kcal/mol), c-KIT1 (−23.9 kcal/mol), c-Myc (−22.0 kcal/mol) G4s, and DNA duplex (−15.0 kcal/mol) systems. These energetic differences coupled with structural differences at the 3′ site explained the different melting temperatures between the G4s, while CX-5461’s lack of intercalation to the duplex explained the difference between the G4s and duplex. Based on the interaction insight, CX-5461 derivatives were designed and docked, showing higher selectivity to the G4s over the duplex.

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Simultaneous cotargeting of ATR and RNA Polymerase I transcription demonstrates synergistic antileukemic effects on acute myeloid leukemia

Cited by 4 publications

References 8 publications

Targeting the DNA damage response in hematological malignancies

Targeting the DNA damage response in hematological malignancies

Recent Advances in Synergistic Antitumor Effects Exploited from the Inhibition of Ataxia Telangiectasia and RAD3-Related Protein Kinase (ATR)

Molecular Dynamics Study on the Binding of an Anticancer DNA G-Quadruplex Stabilizer, CX-5461, to Human Telomeric, c-KIT1, and c-Myc G-Quadruplexes and a DNA Duplex

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