Development of Small Molecules that Specifically Inhibit the D-loop Activity of RAD51

Lv, Wei; Budke, Brian; Kozikowski, Alan P.; Connell, Philip P.

doi:10.1016/j.ijrobp.2016.06.053

Cited by 7 publications

(6 citation statements)

References 28 publications

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“…82 RAD51 inhibition has been shown in preclinical studies to potently activate AID-induced cytotoxicity and to selectively induce cell death in AID-expressing cancer cells. 83 The increasing understanding of the DDR network is leading to many novel therapeutic opportunities. As a cautionary aspect, the knowledge of the therapeutic window and biomarkers of all mentioned inhibitors, including PARP inhibitors, remains limited.…”

Section: Future Ddr Treatment Strategiesmentioning

confidence: 99%

Moving From Poly (ADP-Ribose) Polymerase Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy

Gourley

Balmañà

Ledermann

et al. 2019

JCO

159

133

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The DNA damage response (DDR) pathway coordinates the identification, signaling, and repair of DNA damage caused by endogenous or exogenous factors and regulates cell-cycle progression with DNA repair to minimize DNA damage being permanently passed through cell division. Severe DNA damage that cannot be repaired may trigger apoptosis; as such, the DDR pathway is of crucial importance as a cancer target. Poly (ADP-ribose) polymerase (PARP) is the best-known element of the DDR, and several PARP inhibitors have been licensed. However, there are approximately 450 proteins involved in DDR, and a number of these other targets are being investigated in the laboratory and clinic. We review the most recent evidence for the clinical effect of PARP inhibition in breast and ovarian cancer and explore expansion into the first-line setting and into other tumor types. We critique the evidence for patient selection techniques and summarize what is known about mechanisms of PARP inhibitor resistance. We then discuss what is known about the preclinical rationale for targeting other members of the DDR pathway and the associated tumor cell genetics that may confer sensitivity to these agents. Examples include DNA damage sensors (MLH1), damage signaling molecules (ataxia-telangiectasia mutated; ataxia-telangiectasia mutated–related and Rad3-related; CHK1/2; DNA-dependent protein kinase, catalytic subunit; WEE1; CDC7), or effector proteins for repair (POLQ [also referred to as POLθ], RAD51, poly [ADP-ribose] glycohydrolase). Early-phase clinical trials targeting some of these molecules, either as a single agent or in combination, are discussed. Finally, we outline the challenges that must be addressed to maximize the therapeutic opportunity that targeting DDR provides.

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Section: Future Ddr Treatment Strategiesmentioning

confidence: 99%

Moving From Poly (ADP-Ribose) Polymerase Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy

Gourley

Balmañà

Ledermann

et al. 2019

JCO

159

133

View full text Add to dashboard Cite

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“…IBR2 is among several recently developed RAD51 inhibitors (Huang et al, 2012;Zhu et al, 2013;Balbous et al, 2016;Lv et al, 2016), one of which enhances cell sensitivity to X-irradiation (Lv et al, 2016). Another, B02, when combined with a PARP inhibitor, synergistically enhances the DNAdamaging agent methylmethane sulfonate (Huang et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Synergistic Antiproliferative Activity of the RAD51 Inhibitor IBR2 with Inhibitors of Receptor Tyrosine Kinases and Microtubule Protein

Ferguson

Vincent

Koropatnick

2017

J Pharmacol Exp Ther

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Although cancer cell genetic instability contributes to characteristics that mediate tumorigenicity, it also contributes to the tumor-selective toxicity of some chemotherapy drugs. This synthetic lethality can be enhanced by inhibitors of DNA repair. To exploit this potential Achilles heel, we tested the ability of a RAD51 inhibitor to potentiate the cytotoxicity of chemotherapy drugs. 2-(Benzylsulfonyl)-1-(1-indol-3-yl)-1,2-dihydroisoquinoline (IBR2) inhibits RAD51-mediated DNA double-strand break repair but also enhances cytotoxicity of the Bcr-Abl inhibitor imatinib. The potential for synergy between IBR2 and more drugs was examined in vitro across a spectrum of cancer cell lines from various tissues. Cells were exposed to IBR2 simultaneously with inhibitors of receptor tyrosine kinases, DNA-damaging agents, or microtubule disruptors. IBR2, at concentrations that inhibited proliferation between 0% and 75%, enhanced toxicity by up to 80% of imatinib and regorafenib (targets RAF and kit); epidermal growth factor receptor inhibitors erlotinib, gefitinib, afatinib, and osimertinib; and vincristine, an inhibitor of microtubule function. However, IBR2 antagonized the action of olaparib, cisplatin, melphalan, and irinotecan. A vincristine-resistant squamous cell line was not cross resistant to imatinib, but IBR2 and another RAD51 inhibitor (B02) enhanced imatinib toxicity in this cell line, its HN-5a parent, and the colon cancer line HT-29 by up to 60% and much better than verapamil, a P-glycoprotein inhibitor ( < 0.05). Given the disparate agents the functions of which are enhanced by IBR2, the mechanisms of enhancement may be multimodal. Whether RAD51 is common to these mechanisms remains to be elucidated, but it provides the potential for selectivity to tumor cells.

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“…The Bishop and Connell labs developed a small molecule RAD51 inhibitor, RI-1, that blocks RAD51 binding to ssDNA [200] and radiosensitizes glioma and glioblastoma cells [161,162] . New RAD51 inhibitors have been developed, including one that blocks D-loop formation (strand invasion) and HR but does not affect RAD51 binding to ssDNA or formation of radiation-induced RAD51 foci [201,202] . A recently developed antibody fragment linked to a cell-penetrating peptide blocks RAD51 DNA binding, sensitizes cells to radiation, and is synthetically lethal with PTEN defects in glioma and melanoma cells [163][164][165] .…”

Section: Targeting Hrmentioning

confidence: 99%

Exploiting DNA repair pathways for tumor sensitization, mitigation of resistance, and normal tissue protection in radiotherapy

Nickoloff¹,

Taylor²,

Sharma³

et al. 2021

CDR

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More than half of cancer patients are treated with radiotherapy, which kills tumor cells by directly and indirectly inducing DNA damage, including cytotoxic DNA double-strand breaks (DSBs). Tumor cells respond to these threats by activating a complex signaling network termed the DNA damage response (DDR). The DDR arrests the cell cycle, upregulates DNA repair, and triggers apoptosis when damage is excessive. The DDR signaling and DNA repair pathways are fertile terrain for therapeutic intervention. This review highlights strategies to improve therapeutic gain by targeting DDR and DNA repair pathways to radiosensitize tumor cells, overcome intrinsic and acquired tumor radioresistance, and protect normal tissue. Many biological and environmental factors determine tumor and normal cell responses to ionizing radiation and genotoxic chemotherapeutics. These include cell type and cell cycle phase distribution; tissue/tumor microenvironment and oxygen levels; DNA damage load and quality; DNA repair capacity; and susceptibility to apoptosis or other active or passive cell death pathways. We provide an overview of radiobiological parameters associated with X-ray, proton, and carbon ion radiotherapy; DNA repair and DNA damage signaling pathways; and other factors that regulate tumor and normal cell responses to radiation. We then focus on recent studies exploiting DSB repair pathways to enhance radiotherapy therapeutic gain.

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Development of Small Molecules that Specifically Inhibit the D-loop Activity of RAD51

Cited by 7 publications

References 28 publications

Moving From Poly (ADP-Ribose) Polymerase Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy

Moving From Poly (ADP-Ribose) Polymerase Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy

Synergistic Antiproliferative Activity of the RAD51 Inhibitor IBR2 with Inhibitors of Receptor Tyrosine Kinases and Microtubule Protein

Exploiting DNA repair pathways for tumor sensitization, mitigation of resistance, and normal tissue protection in radiotherapy

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