scholarly journals Early Drug Discovery and Development of Novel Cancer Therapeutics Targeting DNA Polymerase Eta (POLH)

2021 ◽  
Vol 11 ◽  
Author(s):  
David M. Wilson ◽  
Matthew A. J. Duncton ◽  
Caleb Chang ◽  
Christine Lee Luo ◽  
Taxiarchis M. Georgiadis ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Dna Polymerase ◽  
Synthetic Lethality ◽  
Cancer Therapeutics ◽  
Nucleoside Analogs ◽  
Standard Of Care ◽  
Rapid Identification ◽  
Cancer Therapies ◽  
Polymerase Eta

Polymerase eta (or Pol η or POLH) is a specialized DNA polymerase that is able to bypass certain blocking lesions, such as those generated by ultraviolet radiation (UVR) or cisplatin, and is deployed to replication foci for translesion synthesis as part of the DNA damage response (DDR). Inherited defects in the gene encoding POLH (a.k.a., XPV) are associated with the rare, sun-sensitive, cancer-prone disorder, xeroderma pigmentosum, owing to the enzyme’s ability to accurately bypass UVR-induced thymine dimers. In standard-of-care cancer therapies involving platinum-based clinical agents, e.g., cisplatin or oxaliplatin, POLH can bypass platinum-DNA adducts, negating benefits of the treatment and enabling drug resistance. POLH inhibition can sensitize cells to platinum-based chemotherapies, and the polymerase has also been implicated in resistance to nucleoside analogs, such as gemcitabine. POLH overexpression has been linked to the development of chemoresistance in several cancers, including lung, ovarian, and bladder. Co-inhibition of POLH and the ATR serine/threonine kinase, another DDR protein, causes synthetic lethality in a range of cancers, reinforcing that POLH is an emerging target for the development of novel oncology therapeutics. Using a fragment-based drug discovery approach in combination with an optimized crystallization screen, we have solved the first X-ray crystal structures of small novel drug-like compounds, i.e., fragments, bound to POLH, as starting points for the design of POLH inhibitors. The intrinsic molecular resolution afforded by the method can be quickly exploited in fragment growth and elaboration as well as analog scoping and scaffold hopping using medicinal and computational chemistry to advance hits to lead. An initial small round of medicinal chemistry has resulted in inhibitors with a range of functional activity in an in vitro biochemical assay, leading to the rapid identification of an inhibitor to advance to subsequent rounds of chemistry to generate a lead compound. Importantly, our chemical matter is different from the traditional nucleoside analog-based approaches for targeting DNA polymerases.

The “Big Five” Phytochemicals Targeting Cancer Stem Cells: Curcumin, EGCG, Sulforaphane, Resveratrol and Genistein

2020 ◽  
Vol 27 ◽  
Author(s):  
Cord Naujokat ◽  
Dwight L. McKee
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Recurrence ◽  
Cancer Therapeutics ◽  
Cancer Therapies ◽  
Mesenchymal Transition ◽  
Stat3 Signaling ◽  
Xenograft Mice

: Cancer stem cells (CSCs) constitute a subpopulation of tumor cells that possess self-renewal and tumor initiation capacity, and the ability to give rise to the heterogeneous lineages of cancer cells that comprise the tumor. CSCs exhibit intrinsic mechanisms of resistance to virtually all conventional cancer therapeutics, allowing them to survive current cancer therapies and to initiate tumor recurrence and metastasis. Different pathways and mechanisms that confer resistance and survival of CSCs, including activation of the Wnt/β-catenin, Sonic Hedgehog, Notch, PI3K/Akt/mTOR and STAT3 signaling pathways, expression of aldehyde dehydrogenase 1 (ALDH1) and oncogenic microRNAs, and acquisition of epithelial-mesenchymal transition (EMT), have been identified recently. Certain phytochemicals, in particular curcumin, epigallocatechin-3-gallate (EGCG), sulforaphane, resveratrol and genistein have been shown to interfere with these intrinsic CSC pathways in vitro and in human xenograft mice, leading to elimination of CSCs. Moreover, recent clinical trials have demonstrated therapeutic efficacy of the five phytochemicals, alone or in combination with modern cancer therapeutics, and in various types of cancer. Since current cancer therapies fail to eradicate CSCs, leading to cancer recurrence and progression, targeting of CSCs with phytotochemicals such as curcumin, EGCG, sulforaphane, resveratrol and genistein, combined with each other and/or in combination with conventional cytotoxic drugs and novel cancer therapeutics, may offer a novel therapeutic strategy against cancer.

Downregulation Of Deoxycytidine Kinase In Cytarabine-Resistant Mantle Cell Lymphoma Cells Confers Cross-Resistance To Nucleoside Analogs Fludarabine, Gemcitabine and Cladribine, But Not To Other Classes Of Anti-Lymphoma Agents

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3835-3835 ◽  
Author(s):  
Magdalena Klanova ◽  
Lucie Lorkova ◽  
Ondrej Vit ◽  
Bokang Maswabi ◽  
Jan Molinsky ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cell Lymphoma ◽  
Nucleoside Analogs ◽  
Standard Of Care ◽  
Cross Resistance ◽  
Experimental Therapy ◽  
First Line ◽  
Mantle Cell ◽  
Anti Tumor Activity

Abstract Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin lymphoma associated with poor prognosis. In recent years several studies brought evidence that implementation of high-dose cytarabine (ara-C) into induction therapy, e.g. by sequential chemotherapy by CHOP and DHAP regimens, induced higher response rate and prolonged progression-free survival compared to R-CHOP-only. Based on these results, implementation of ara-C into induction therapy became standard of care for all newly diagnosed younger MCL patients. Despite considerable improvement, however, many MCL patients relapse even after ara-C-based first-line regimen. There is no second-line standard-of-care for relapsed/refractory MCL. Currently available treatment approaches include fludarabine, gemcitabine, cisplatin, temsirolimus, bortezomib, bendamustine and many investigational agents, e.g. ibrutinib. By long-term co-culture of 5 cytarabine-sensitive MCL cell lines (Jeko-1, Mino, Rec-1, Hbl-2 and Granta-519, designated as CTRL cell lines) with increasing doses of ara-C (up to 50uM) we derived 5 respective ara-C-resistant (R) MCL subclones. Gene expression analyses of R subclones compared to CTRL cell lines by IlluminaHumanRef-12 BeadChips revealed that the only deregulated (namely downregulated) gene accross all 5 datasets was deoxycytidine-kinase (DCK). Marked downregulation of DCK was confirmed by western blotting. In vitro proliferation assay by WST-8 revealed cross-resistance of R subclones to all tested nucleoside analogs (namely gemcitabine, fludarabine and cladribine; 20-1000x compared to sensitivity of respective CTRL cell lines). Importantly, in vitro sensitivity of R subclones to the other tested anti-tumor agents (i.e. other than antinucleotides) including bortezomib, bendamustine, temsirolimus, cisplatin, etoposide, doxorubicin, ibrutinib, ABT-737, olaparib, roscovitine, homoharringtonine, vorinostat and TRAIL was not significantly changed compared to CTRL cell lines. Similarly, R subclones retained in vitro sensitivity to anti-CD20 monoclonal antibodies rituximab and ofatumumab as determined by standard 51Cr release assays. Experimental therapy of Jeko-1 and Mino-xenografted mice (immunodeficient NSG mice, each cohort comprising 8 animals) with single-agent fludarabine, gemcitabine, cisplatin, temsirolimus, bendamustine and rituximab confirmed the anticipated loss of anti-tumor activity (as measured by overall survival of experimental animals) of the nucleoside analogs in mice transplanted with R subclones compared to mice transplanted with CTRL cell lines. Anti-tumor activity of cisplatin, temsirolimus, bendamustine and rituximab remained comparable between experimental therapy of R subclone and CTRL cell line xenografts. In conclusion our data show that acquired resistance of MCL cells to ara-C is associated with marked downregulation of mRNA and protein expression of DCK, enzyme of the nucleotide salvage pathway responsible for phosphorylation (=activation) of most nucleoside analogs used in anti-cancer therapy. Indeed, all R subclones (compared to CTRL cell lines) were cross-resistant to fludarabine, gemcitabine and cladribine, but remained sensitive to other classes of anti-lymphoma agents, including genotoxic drugs and targeted agents. Despite the fact that these preclinical data need definite confirmation on primary patient samples, the results do suggest that nucleoside analogs should not be used for the therapy of MCL patients, who relaps after ara-C-based first-line regimen. Financial Support: IGA-MZ: NT13201-4/2012, GA-UK 446211, UNCE 204021, PRVOUK-27/LF1/1, PRVOUK P24/LF1/3, SVV-2013-266509 Disclosures: No relevant conflicts of interest to declare.

scholarly journals Recombination and Pol ζ Rescue Defective DNA Replication upon Impaired CMG Helicase—Pol ε Interaction

2020 ◽  
Vol 21 (24) ◽  
pp. 9484
Author(s):  
Milena Denkiewicz-Kruk ◽  
Malgorzata Jedrychowska ◽  
Shizuko Endo ◽  
Hiroyuki Araki ◽  
Piotr Jonczyk ◽  
...  
Keyword(s):  
Dna Replication ◽  
Dna Polymerase ◽  
Synthetic Lethality ◽  
Replication Initiation ◽  
Recombination Rates ◽  
Dna Polymerase Epsilon ◽  
Dna Replication Initiation ◽  
Leading Strand

The CMG complex (Cdc45, Mcm2–7, GINS (Psf1, 2, 3, and Sld5)) is crucial for both DNA replication initiation and fork progression. The CMG helicase interaction with the leading strand DNA polymerase epsilon (Pol ε) is essential for the preferential loading of Pol ε onto the leading strand, the stimulation of the polymerase, and the modulation of helicase activity. Here, we analyze the consequences of impaired interaction between Pol ε and GINS in Saccharomyces cerevisiae cells with the psf1-100 mutation. This significantly affects DNA replication activity measured in vitro, while in vivo, the psf1-100 mutation reduces replication fidelity by increasing slippage of Pol ε, which manifests as an elevated number of frameshifts. It also increases the occurrence of single-stranded DNA (ssDNA) gaps and the demand for homologous recombination. The psf1-100 mutant shows elevated recombination rates and synthetic lethality with rad52Δ. Additionally, we observe increased participation of DNA polymerase zeta (Pol ζ) in DNA synthesis. We conclude that the impaired interaction between GINS and Pol ε requires enhanced involvement of error-prone Pol ζ, and increased participation of recombination as a rescue mechanism for recovery of impaired replication forks.

scholarly journals Facilitating Drug Discovery in Breast Cancer by Virtually Screening Patients Using In Vitro Drug Response Modeling

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 885
Author(s):  
Robert F. Gruener ◽  
Alexander Ling ◽  
Ya-Fang Chang ◽  
Gladys Morrison ◽  
Paul Geeleher ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Discovery ◽  
Cell Line ◽  
Drug Response ◽  
Drug Efficacy ◽  
Standard Of Care ◽  
Breast Cancer Patients ◽  
Response Modeling

(1) Background: Drug imputation methods often aim to translate in vitro drug response to in vivo drug efficacy predictions. While commonly used in retrospective analyses, our aim is to investigate the use of drug prediction methods for the generation of novel drug discovery hypotheses. Triple-negative breast cancer (TNBC) is a severe clinical challenge in need of new therapies. (2) Methods: We used an established machine learning approach to build models of drug response based on cell line transcriptome data, which we then applied to patient tumor data to obtain predicted sensitivity scores for hundreds of drugs in over 1000 breast cancer patients. We then examined the relationships between predicted drug response and patient clinical features. (3) Results: Our analysis recapitulated several suspected vulnerabilities in TNBC and identified a number of compounds-of-interest. AZD-1775, a Wee1 inhibitor, was predicted to have preferential activity in TNBC (p < 2.2 × 10−16) and its efficacy was highly associated with TP53 mutations (p = 1.2 × 10−46). We validated these findings using independent cell line screening data and pathway analysis. Additionally, co-administration of AZD-1775 with standard-of-care paclitaxel was able to inhibit tumor growth (p < 0.05) and increase survival (p < 0.01) in a xenograft mouse model of TNBC. (4) Conclusions: Overall, this study provides a framework to turn any cancer transcriptomic dataset into a dataset for drug discovery. Using this framework, one can quickly generate meaningful drug discovery hypotheses for a cancer population of interest.

scholarly journals Generative AI Design and Exploration of Nucleoside Analogs

2021 ◽  
Author(s):  
Damien Dablain ◽  
Geoffrey Siwo ◽  
Nitesh Chawla
Keyword(s):  
Drug Discovery ◽  
Prebiotic Chemistry ◽  
Antiviral Drug ◽  
Nucleoside Analogs ◽  
Building Blocks ◽  
Generative Models ◽  
Chemical Transformations ◽  
Generative Design ◽  
Wide Range

Nucleosides are fundamental building blocks of DNA and RNA in all life forms and viruses. In addition, natural nucleosides and their analogs are critical in prebiotic chemistry, innate immunity, signaling, antiviral drug discovery and artificial synthesis of DNA / RNA sequences. Combined with the fact that quantitative structure activity relationships (QSAR) have been widely performed to understand their antiviral activity, nucleoside analogs could be used to benchmark generative molecular design. Here, we undertake the first generative design of nucleoside analogs using an approach that we refer to as the Conditional Randomized Transformer (CRT). We also benchmark our model against five previously published molecular generative models. We demonstrate that AI-generated molecules include nucleoside analogs that are of significance in a wide range of areas including prebiotic chemistry, antiviral drug discovery and synthesis of oligonucleotides. Our results show that CRT explores distinct molecular spaces and chemical transformations, some of which are similar to those undertaken by nature and medicinal chemists. Finally, we demonstrate the potential application of the CRT model in the generative design of molecules conditioned on Remdesivir and Molnupiravir as well as other nucleoside analogs with in vitro activity against SARS-CoV-2. One-Sentence Summary: Generative design of nucleoside analogs relevant to antiviral drug discovery, prebiotic chemistry and synthetic biology.

scholarly journals To Discover the Efficient and Novel Drug Targets in Human Cancers Using CRISPR/Cas Screening and Databases

2021 ◽  
Vol 22 (22) ◽  
pp. 12322
Author(s):  
Iichiroh Onishi ◽  
Kouhei Yamamoto ◽  
Yuko Kinowaki ◽  
Masanobu Kitagawa ◽  
Morito Kurata
Keyword(s):  
Drug Targets ◽  
Gene Editing ◽  
Synthetic Lethality ◽  
Cancer Therapies ◽  
Human Cancers ◽  
Genetic Abnormalities ◽  
Ideal Tool ◽  
Novel Drug ◽  
Novel Drug Targets

CRISPR/Cas has emerged as an excelle nt gene-editing technology and is used worldwide for research. The CRISPR library is an ideal tool for identifying essential genes and synthetic lethality targeted for cancer therapies in human cancers. Synthetic lethality is defined as multiple genetic abnormalities that, when present individually, do not affect function or survival, but when present together, are lethal. Recently, many CRISPR libraries are available, and the latest libraries are more accurate and can be applied to few cells. However, it is easier to efficiently search for cancer targets with their own screenings by effectively using databases of CRISPR screenings, such as Depmap portal, PICKLES (Pooled In-Vitro CRISPR Knockout Library Essentiality Screens), iCSDB, Project Score database, and CRISP-view. This review will suggest recent optimal CRISPR libraries and effective databases for Novel Approaches in the Discovery and Design of Targeted Therapies.

scholarly journals Advances in Cancer Therapeutics: Conventional Thermal Therapy to Nanotechnology-Based Photothermal Therapy

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1174
Author(s):  
Sangeeta Kumari ◽  
Nilesh Sharma ◽  
Shivendra V. Sahi
Keyword(s):  
Photothermal Therapy ◽  
Critical Appraisal ◽  
Cancer Therapeutics ◽  
Thermal Therapy ◽  
Cancer Therapies ◽  
Thermal Therapies ◽  
Promising Avenue

In this review, advancement in cancer therapy that shows a transition from conventional thermal therapies to laser-based photothermal therapies is discussed. Laser-based photothermal therapies are gaining popularity in cancer therapeutics due to their overall outcomes. In photothermal therapy, light is converted into heat to destruct the various types of cancerous growth. The role of nanoparticles as a photothermal agent is emphasized in this review article. Magnetic, as well as non-magnetic, nanoparticles have been effectively used in the photothermal-based cancer therapies. The discussion includes a critical appraisal of in vitro and in vivo, as well as the latest clinical studies completed in this area. Plausible evidence suggests that photothermal therapy is a promising avenue in the treatment of cancer.

Novel Mechanistic Insights into the Anti-cancer Mode of Arsenic Trioxide

2020 ◽  
Vol 20 (2) ◽  
pp. 115-129 ◽  
Author(s):  
Md Wahiduzzaman ◽  
Akinobu Ota ◽  
Yoshitaka Hosokawa
Keyword(s):  
Arsenic Trioxide ◽  
Molecular Mechanisms ◽  
Cancer Therapeutics ◽  
Cancer Drug ◽  
Clinical Settings ◽  
Cancer Therapies ◽  
Cellular Models ◽  
Anti Cancer ◽  
Cancer Phenotype

Arsenic, a naturally-occurring toxic element, and a traditionally-used drug, has received a great deal of attention worldwide due to its curative anti-cancer properties in patients with acute promyelocytic leukemia. Among the arsenicals, arsenic trioxide has been most widely used as an anti-cancer drug. Recent advances in cancer therapeutics have led to a paradigm shift away from traditional cytotoxic drugs towards the targeting of proteins closely associated with driving the cancer phenotype. Due to the diverse anti-cancer effects of ATO on different types of malignancies, numerous studies have made efforts to uncover the mechanisms of ATO-induced tumor suppression. From in vitro cellular models to studies in clinical settings, ATO has been extensively studied. The outcomes of these studies have opened doors to establishing improved molecular-targeted therapies for cancer treatment. The efficacy of ATO has been augmented by combination with other drugs. In this review, we discuss recent arsenic-based cancer therapies and summarize the novel underlying molecular mechanisms of the anti-cancer effects of ATO.

scholarly journals Advancements in 3D Cell Culture Systems for Personalizing Anti-Cancer Therapies

2021 ◽  
Vol 11 ◽  
Author(s):  
Andrew M. K. Law ◽  
Laura Rodriguez de la Fuente ◽  
Thomas J. Grundy ◽  
Guocheng Fang ◽  
Fatima Valdes-Mora ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
3D Culture ◽  
3D Cell Culture ◽  
Cancer Therapeutics ◽  
Drug Efficacy ◽  
Cancer Drug ◽  
Cancer Therapies ◽  
Anti Cancer

Over 90% of potential anti-cancer drug candidates results in translational failures in clinical trials. The main reason for this failure can be attributed to the non-accurate pre-clinical models that are being currently used for drug development and in personalised therapies. To ensure that the assessment of drug efficacy and their mechanism of action have clinical translatability, the complexity of the tumor microenvironment needs to be properly modelled. 3D culture models are emerging as a powerful research tool that recapitulates in vivo characteristics. Technological advancements in this field show promising application in improving drug discovery, pre-clinical validation, and precision medicine. In this review, we discuss the significance of the tumor microenvironment and its impact on therapy success, the current developments of 3D culture, and the opportunities that advancements that in vitro technologies can provide to improve cancer therapeutics.

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