Development of PARP inhibitors in advanced prostate cancer

Bourlon, Maria Teresa; Valdez, Paola; Castro, Elena

doi:10.1177/17588359231221337

Cited by 6 publications

(1 citation statement)

References 75 publications

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“…Given the paramount roles of PARylating ARTDs enzymes, the discovery of PARP inhibitors has been greatly incentivized since the '90s [48] and culminated in 2014 with the approval of Olaparib as treatment for advanced ovarian cancer with BRCA germline mutation [49]. Over the years, multiple compound scaffolds have been developed [50,51] and other clinical approvals have followed for the treatment of ovarian, breast and prostate cancers [52][53][54]. All the approved drugs and most of the developed PARP inhibitors bind to the conserved nicotinamide (NI) pocket of the ART domain, interacting with the protein in the same fashion as the nicotinamide moiety of NAD + .…”

Section: Introductionmentioning

confidence: 99%

Substitutions at the C-8 position of quinazolin-4-ones improve the potency of nicotinamide site binding tankyrase inhibitors

Bosetti,

Kampasis,

Galera-Prat

et al. 2024

Preprint

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Human diphtheria toxin-like ADP-ribosyltransferases, PARPs and tankyrases, transfer ADP-ribosyl groups to other macromolecules, thereby controlling various signaling events in cells. They are considered promising drug targets, especially in oncology, and some small molecule inhibitors have already been developed. These inhibitors typically interact with the nicotinamide binding site and extend along the NAD+binding groove of the catalytic domain. Quinazolin-4-ones have been explored as promising scaffolds for such inhibitors and we have identified a new position within the catalytic domain that has not been extensively studied yet. In this study, we investigate larger substituents at the C-8 position and, using X-ray crystallography, we demonstrate that nitro- and diol-substituents engage in new interactions with TNKS2, improving both affinity and selectivity. Both nitro- and diol-substituents exhibit intriguing inhibition of TNKS2, with compound49displaying an IC50of 65 nM, while compound40’s IC50value is 14 nM. Both analogues show efficacy in cell assays and attenuate the tankyrase-controlled Wnt/β-catenin signaling with sub-micromolar IC50. When tested against a wider panel of enzymes, compound40displayed high selectivity towards tankyrases, whereas49also inhibited other PARPs. The results offer new insights for inhibitor development targeting tankyrases and PARPs by focusing on the subsite between a mobile active site loop and the canonical nicotinamide binding site.

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Section: Introductionmentioning

confidence: 99%

Substitutions at the C-8 position of quinazolin-4-ones improve the potency of nicotinamide site binding tankyrase inhibitors

Bosetti,

Kampasis,

Galera-Prat

et al. 2024

Preprint

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New-generation androgen receptor signaling inhibitors (ARSIs) in metastatic hormone-sensitive prostate cancer (mHSPC): pharmacokinetics, drug-drug interactions (DDIs), and clinical impact

Gasperoni,

Giunta,

Montanari

et al. 2024

Expert Opinion on Drug Metabolism & Toxicology

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Contemporary Diagnostic Reporting for Prostatic Adenocarcinoma: Morphologic Aspects, Molecular Correlates, and Management Perspectives

Muthusamy,

Smith

2024

Advances in Anatomic Pathology

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The diagnosis and reporting of prostatic adenocarcinoma have evolved from the classic framework promulgated by Dr Donald Gleason in the 1960s into a complex and nuanced system of grading and reporting that nonetheless retains the essence of his remarkable observations. The criteria for the “Gleason patterns” originally proposed have been continually refined by consensuses in the field, and Gleason scores have been stratified into a patient-friendly set of prognostically validated and widely adopted Grade Groups. One product of this successful grading approach has been the opportunity for pathologists to report diagnoses that signal carefully personalized management, placing the surgical pathologist’s interpretation at the center of patient care. At one end of the continuum of disease aggressiveness, personalized diagnostic care means to sub-stratify patients with more indolent disease for active surveillance, while at the other end of the continuum, reporting histologic markers signaling aggression allows sub-stratification of clinically significant disease. Whether contemporary reporting parameters represent deeper nuances of more established ones (eg, new criteria and/or quantitation of Gleason patterns 4 and 5) or represent additional features reported alongside grade (intraductal carcinoma, cribriform patterns of carcinoma), assessment and grading have become more complex and demanding. Herein, we explore these newer reporting parameters, highlighting the state of knowledge regarding morphologic, molecular, and management aspects. Emphasis is made on the increasing value and stakes of histopathologists’ interpretations and reporting into current clinical risk stratification and treatment guidelines.

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Development of PARP inhibitors in advanced prostate cancer

Cited by 6 publications

References 75 publications

Substitutions at the C-8 position of quinazolin-4-ones improve the potency of nicotinamide site binding tankyrase inhibitors

Substitutions at the C-8 position of quinazolin-4-ones improve the potency of nicotinamide site binding tankyrase inhibitors

New-generation androgen receptor signaling inhibitors (ARSIs) in metastatic hormone-sensitive prostate cancer (mHSPC): pharmacokinetics, drug-drug interactions (DDIs), and clinical impact

Contemporary Diagnostic Reporting for Prostatic Adenocarcinoma: Morphologic Aspects, Molecular Correlates, and Management Perspectives

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