Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides

Waszkowycz, Bohdan; Smith, Kate; McGonagle, Alison E.; Jordan, Allan M.; Acton, Ben; Fairweather, Emma; Griffiths, Louise A.; Hamilton, Niall M.; Hamilton, Nicola; Hitchin, James R.; Hutton, Colin; James, Dominic I.; Jones, Clifford D.; Jones, Stuart; Mould, Daniel P.; Small, Helen; Stowell, Alexandra; Tucker, J.A.; Waddell, Ian D.; Ogilvie, Donald

doi:10.1021/acs.jmedchem.8b01407

Cited by 24 publications

(23 citation statements)

References 35 publications

(73 reference statements)

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“…Future efforts in the development of small molecule inhibitors will hopefully produce new probes to study the (patho-)physiological roles of these fascinating enzymes as well as lead to new drugs with therapeutic applications. The potential of such an approach was highlighted over recent years with the development of PARG inhibitors finding their application in cancer therapy (James et al 2016;Gravells et al 2017;Waszkowycz et al 2018).…”

Section: Discussionmentioning

confidence: 99%

“…In canonical PARGs, ligand binding is further stabilized by a highly conserved tyrosine (Tyr795 in humans) that coordinates O5 ′ and edge stacks with the adenosine moiety (Kim et al 2012;Tucker et al 2012;Lambrecht et al 2015). Recently, these highly specific properties of the adenine-binding pocket were utilized for the development of a series of high-potency, competitive inhibitors (Waszkowycz et al 2018). Further along the ligand, the diphosphate-binding loop coordinates both the diphosphate and distal ribose and participates in forcing a strained conformation in this part of the molecule.…”

Section: Structure and Function Of Parg-like Hydrolasesmentioning

confidence: 99%

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(ADP-ribosyl)hydrolases: structure, function, and biology

2020

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ADP-ribosylation is an intricate and versatile posttranslational modification involved in the regulation of a vast variety of cellular processes in all kingdoms of life. Its complexity derives from the varied range of different chemical linkages, including to several amino acid side chains as well as nucleic acids termini and bases, it can adopt. In this review, we provide an overview of the different families of (ADP-ribosyl)hydrolases. We discuss their molecular functions, physiological roles, and influence on human health and disease. Together, the accumulated data support the increasingly compelling view that (ADP-ribosyl)hydrolases are a vital element within ADP-ribosyl signaling pathways and they hold the potential for novel therapeutic approaches as well as a deeper understanding of ADP-ribosylation as a whole.

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Section: Discussionmentioning

confidence: 99%

Section: Structure and Function Of Parg-like Hydrolasesmentioning

confidence: 99%

(ADP-ribosyl)hydrolases: structure, function, and biology

2020

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“…Tetracycline-screened FBS (TET FBS) was purchased from GE Healthcare (Chicago, IL) and doxycycline from Thermo Fisher Scientific (Manassas, VA). PDD00017272 (referred to as PDDX elsewhere in the manuscript was synthesized at Cancer Research UK Manchester Institute (compound 34 f) 24 . The ammonium salt of ADP-HPD dehydrate was purchased from Calbiochem (San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

“…A thorough evaluation of PARG function in prostate cancer was hampered by a lack of stable and bioavailable inhibitors. Recently, we synthesized and characterized a number of novel and specific PARG inhibitors, including PDD00017272 24 . In this report, we tested whether androgen deprivation synergized with PARG inhibition to suppress prostate cancer cell growth.…”

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confidence: 99%

Androgen Receptor and Poly(ADP-ribose) Glycohydrolase Inhibition Increases Efficiency of Androgen Ablation in Prostate Cancer Cells

Zhang

Lai

Vasquez

et al. 2020

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There is mounting evidence of androgen receptor signaling inducing genome instability and changing DNA repair capacity in prostate cancer cells. Expression of genes associated with base excision repair (BER) is increased with prostate cancer progression and correlates with poor prognosis. Poly(ADPribose) polymerase (pARp) and poly(ADp-ribose) glycohydrolase (pARG) are key enzymes in BeR that elongate and degrade pAR polymers on target proteins. While pARp inhibitors have been tested in clinical trials and are a promising therapy for prostate cancer patients with TMPRSS2-ERG fusions and mutations in DNA repair genes, PARG inhibitors have not been evaluated. We show that PARG is a direct androgen receptor (AR) target gene. AR is recruited to the pARG locus and induces pARG expression. Androgen ablation combined with PARG inhibition synergistically reduces BER capacity in independently derived LNCaP and LAPC4 prostate cancer cell lines. A combination of PARG inhibition with androgen ablation or with the DNA damaging drug, temozolomide, significantly reduces cellular proliferation and increases DNA damage. PARG inhibition alters AR transcriptional output without changing AR protein levels. thus, AR and pARG are engaged in reciprocal regulation suggesting that the success of androgen ablation therapy can be enhanced by PARG inhibition in prostate cancer patients. Late stage prostate cancers are treated with radiation and other cytotoxic therapies. It was observed that androgen ablation sensitizes prostate tumors to radiation and chemotherapy in prostate cancer patients 1-3. Prostate tumors with high androgen receptor (AR) transcriptional output have increased expression of DNA repair genes in general, and base excision repair (BER) associated proteins in particular 4,5. Conversely, AR upregulates pathways in prostate cancer that increase genomic instability, such as the TMPRSS2-ERG gene fusion, which is present in a significant part of advanced prostate cancers 5,6. Importantly, inhibition of poly(ADP-ribose) polymerase 1 (PARP1) significantly increases levels of DNA damage in such tumors 7 and is currently being tested in clinical trials in metastatic castration resistant prostate cancer (CRPC) with somatic or germline mutations in DNA repair genes. The PARP inhibitors rucaparib (NCT02952534, NCT03533946 and NCT03413995) and olaparib (NCT02316197, NCT03012321, NCT03787680, NCT03432897 and others) have been tested in clinical trials and were granted breakthrough designation by the U.S. Food and Drug Administration (FDA) for metastatic CRPC. Poly(ADP-ribose) glycohydrolase (PARG) and PARP1 are key enzymes required for DNA repair and maintenance of genomic stability. Poly ADP-ribose (PAR) is a heterogeneous branched polymer of ADP-ribose that is attached to proteins in response to various stimuli by a dynamic process called PARylation. PARylation regulates DNA damage detection and repair as PAR acts as a loading platform to recruit a variety of DNA repair factors, in a non-covalent fashion, to the DNA lesions. Multiple ...

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“…We recently described a series of quinazolinedione inhibitors of the DNA repair enzyme poly-ADP ribose glycohydrolase (PARG), typified by 1 and 2 . 1 During the optimisation of these molecules, we discovered that these compounds suffered from a short half-life when exposed to human liver microsomes. Generally, compounds bearing two benzyl or heteroarylmethyl substituents, such as 1 , were highly potent but degraded more quickly in in vitro microsomal stability assays than those with a single pendant aryl moiety, such as 2 , which were around ten-fold less potent.…”

mentioning

confidence: 99%