Targeting the OB‐Folds of Replication Protein A with Small Molecules

Granadillo, Victor J. Anciano; Earley, Jennifer N.; Shuck, Sarah C.; Georgiadis, Millie M.; Fitch, Richard W.; Turchi, John J.

doi:10.4061/2010/304035

Cited by 24 publications

(27 citation statements)

References 36 publications

(55 reference statements)

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“…Prior to the discovery of RPA-protein inhibitors, inhibitors of RPA-ssDNA interaction have been characterized and have been shown to be cytotoxic and act with synergy with cisplatin, displaying the potential for RPA as a drug target (46, 47). The discovery of several other DBD-F binding proteins further increased the potential of such an inhibition (11, 14).…”

Section: Discussionmentioning

confidence: 99%

RPA Inhibition Increases Replication Stress and Suppresses Tumor Growth

et al. 2014

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The ATR/Chk1 pathway is a critical surveillance network that maintains genomic integrity during DNA replication by stabilizing the replication forks during normal replication to avoid replication stress. One of the many differences between normal cells and cancer cells is the amount of replication stress that occurs during replication. Cancer cells with activated oncogenes generate increased levels of replication stress. This creates an increased dependency on the ATR/Chk1 pathway in cancer cells and opens up an opportunity to preferentially kill cancer cells by inhibiting this pathway. In support of this idea, we have identified a small molecule termed HAMNO ((1Z)-1-[(2-hydroxyanilino)methylidene]naphthalen-2-one), a novel protein interaction inhibitor of replication protein A (RPA), a protein involved in the ATR/Chk1 pathway. HAMNO selectively binds the N-terminal domain of RPA70, effectively inhibiting critical RPA protein interactions which rely on this domain. HAMNO inhibits both ATR autophosphorylation and phosphorylation of RPA32 Ser33 by ATR. By itself, HAMNO treatment creates DNA replication stress in cancer cells that are already experiencing replication stress, but not in normal cells, and it acts synergistically with etoposide to kill cancer cells in vitro and slow tumor growth in vivo. Thus, HAMNO illustrates how RPA inhibitors represent candidate therapeutics for cancer treatment, providing disease selectivity in cancer cells by targeting their differential response to replication stress.

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Section: Discussionmentioning

confidence: 99%

RPA Inhibition Increases Replication Stress and Suppresses Tumor Growth

et al. 2014

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“…This separation of function can be exploited by using chemical probes that exclusively interfere with the DNA repair pathway and that, in conjunction with DNA-damaging agents, would offer a new possibility for cancer treatment. Our group has previously reported both reversible and irreversible chemical inhibitors of RPA [25–28]. The reversible inhibitor TDRL-505 exhibits synergistic effects with DNA damaging agents in a lung cancer cell model.…”

Section: Introductionmentioning

confidence: 99%

Chemical inhibitor targeting the replication protein A–DNA interaction increases the efficacy of Pt-based chemotherapy in lung and ovarian cancer

Mishra

Dormi

Turchi

et al. 2015

Biochemical Pharmacology

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Platinum-based chemotherapeutics exert their therapeutic efficacy via the formation of DNA adducts which interfere with DNA replication, transcription and cell division and ultimately induce cell death. Repair and tolerance of these Pt-DNA lesions by nucleotide excision repair (NER) and homologous recombination (HR) can substantially reduce the effectiveness of therapy. Inhibition of these repair pathways, therefore, holds the potential to sensitize cancer cells to Pt treatment and increase clinical efficacy. Replication Protein A (RPA) plays essential roles in both NER and HR, along with its role in DNA replication and DNA damage checkpoint activation. Each of these functions is, in part, mediated by RPA binding to single-stranded DNA (ssDNA). Here we report the synthesis and characterization of novel derivatives of RPA small molecule inhibitors and their activity in models of epithelial ovarian cancer (EOC) and non-small cell lung cancer (NSCLC). We have synthesized analogs of our previously reported RPA inhibitor TDRL-505 and determined the structure activity relationships. These data led us to the identification of TDRL-551, which exhibited a greater than 2-fold increase in in vitro activity. TDRL-551 showed synergy with Pt in tissue culture models of EOC and in vivo efficacy, as a single agent and in combination with platinum, in a NSCLC xenograft model. These data demonstrate the utility of RPA inhibition in EOC and NSCLC and the potential in developing novel anticancer therapeutics that target RPA-DNA interactions.

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“…These data suggest a defect of RPA activity in responding to replication stress in the Bcas2 mNull zygotes. To examine the involvement of the RPA complex in DNA repair at the first mouse cell cycle, normal zygotes were recovered at 23 h post-hCG (PN2) and either injected with Rpa2 mutant (S4A/S8A, Thr21A or S33A) mRNA or treated with TDRL-505, an inhibitor blocking the formation of RPA-ssDNA (Anciano Granadillo et al, 2010;Shuck and Turchi, 2010). After culturing for 7-8 h, the embryos were stained for γH2AX.…”

Section: Bcas2 Functions In Mouse Zygotes Through the Rpa Complexmentioning

confidence: 99%

Maternal BCAS2 protects genomic integrity in mouse early embryonic development

Wang

Xiang

et al. 2015

Development

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Mammalian early embryos maintain accurate genome integrity for proper development within a programmed timeline despite constant assaults on their DNA by replication, DNA demethylation and genetic defects transmitted from germ cells. However, how genome integrity is safeguarded during mammalian early embryonic development remains unclear. BCAS2 (breast carcinoma amplified sequence 2), a core component of the PRP19 complex involved in pre-mRNA splicing, plays an important role in the DNA damage response through the RPA complex, a key regulator in the maintenance of genome integrity. Currently, the physiological role of BCAS2 in mammals is unknown. We now report that BCAS2 responds to endogenous and exogenous DNA damage in mouse zygotes. Maternal depletion of BCAS2 compromises the DNA damage response in early embryos, leading to developmental arrest at the two-to four-cell stage accompanied by the accumulation of damaged DNA and micronuclei. Furthermore, BCAS2 mutants that are unable to bind RPA1 fail in DNA repair during the zygotic stage. In addition, phosphorylated RPA2 cannot localise to the DNA damage sites in mouse zygotes with disrupted maternal BCAS2. These data suggest that BCAS2 might function through the RPA complex during DNA repair in zygotes. Together, our results reveal that maternal BCAS2 maintains the genome integrity of early embryos and is essential for female mouse fertility.

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Targeting the OB‐Folds of Replication Protein A with Small Molecules

Cited by 24 publications

References 36 publications

RPA Inhibition Increases Replication Stress and Suppresses Tumor Growth

RPA Inhibition Increases Replication Stress and Suppresses Tumor Growth

Chemical inhibitor targeting the replication protein A–DNA interaction increases the efficacy of Pt-based chemotherapy in lung and ovarian cancer

Maternal BCAS2 protects genomic integrity in mouse early embryonic development

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