Combination of Selective PARP3 and PARP16 Inhibitory Analogues of Latonduine A Corrects F508del-CFTR Trafficking

Centko, Ryan M.; Carlile, Graeme W.; Barne, Isabel; Patrick, Brian O.; Blagojević, Polina D.; Thomas, David Y.; Andersen, Raymond J.

doi:10.1021/acsomega.0c02467

Cited by 12 publications

(21 citation statements)

References 42 publications

(122 reference statements)

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“…In pathologic conditions, chlorine ions cannot flux out of the cells, and this determines the accumulation of thick mucus in the lungs. In order to separate the PARP16 and PARP3 inhibitory properties of 73 , in 2020, Thomas, Andersen et al 148 synthesized a library of ∼30 analogues characterized by a simplified structure based on a 2,3,4,5-tetrahydro- H -benzo[ c ]azepin-1-one core differently decorated on the two rings ( Figure 20 ). All of the compounds were preliminary tested at 10 μM against PARP3 and PARP16.…”

Section: Mono-art Inhibitorsmentioning

confidence: 99%

Medicinal Chemistry Perspective on Targeting Mono-ADP-Ribosylating PARPs with Small Molecules

et al. 2022

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Major advances have recently defined functions for human mono-ADP-ribosylating PARP enzymes (mono-ARTs), also opening up potential applications for targeting them to treat diseases. Structural biology combined with medicinal chemistry has allowed the design of potent small molecule inhibitors which typically bind to the catalytic domain. Most of these inhibitors are at the early stages, but some have already a suitable profile to be used as chemical tools. One compound targeting PARP7 has even progressed to clinical trials. In this review, we collect inhibitors of mono-ARTs with a typical “H–Y−Φ” motif (Φ = hydrophobic residue) and focus on compounds that have been reported as active against one or a restricted number of enzymes. We discuss them from a medicinal chemistry point of view and include an analysis of the available crystal structures, allowing us to craft a pharmacophore model that lays the foundation for obtaining new potent and more specific inhibitors.

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Section: Mono-art Inhibitorsmentioning

confidence: 99%

Medicinal Chemistry Perspective on Targeting Mono-ADP-Ribosylating PARPs with Small Molecules

et al. 2022

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“…These data strongly confirmed the authors’ hypothesis that the F508del-CFTR rescue exhibited by 28 and 31 could be caused by the dual-target simultaneous inhibition of PARP-3 and PARP-16. 158 However, the mechanism of CFTR rescue enhanced by PARPi needs to be explained in more detail in order to anticipate possible side effects.…”

Section: Targeting Poly-adp Ribose Polymerasesmentioning

confidence: 99%

Proteostasis Regulators in Cystic Fibrosis: Current Development and Future Perspectives

et al. 2022

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In cystic fibrosis (CF), the deletion of phenylalanine 508 (F508del) in the CF transmembrane conductance regulator (CFTR) leads to misfolding and premature degradation of the mutant protein. These defects can be targeted with pharmacological agents named potentiators and correctors. During the past years, several efforts have been devoted to develop and approve new effective molecules. However, their clinical use remains limited, as they fail to fully restore F508del-CFTR biological function. Indeed, the search for CFTR correctors with different and additive mechanisms has recently increased. Among them, drugs that modulate the CFTR proteostasis environment are particularly attractive to enhance therapy effectiveness further. This Perspective focuses on reviewing the recent progress in discovering CFTR proteostasis regulators, mainly describing the design, chemical structure, and structure–activity relationships. The opportunities, challenges, and future directions in this emerging and promising field of research are discussed, as well.

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“… 80 Synthetic analogues of the marine natural product latonduine A also demonstrated to rescue F508del-CFTR traffic by inhibiting function of Poly(ADP-ribose) polymerase 3 and 16 (PARP3 and PARP16). 81 Novel pyrrolothiazole derivative compounds were recently synthesized and their ability to rescue F508del-CFTR was evaluated in a small-scale screen. 82 Among these, compound 44 rescued F508del-CFTR processing and function being additive to VX-809 but not to VX-661.…”

Section: Cftr Modulator Drugs and Personalized Medicinementioning

confidence: 99%

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

Pinto¹,

Silva²,

Figueira³

et al. 2021

JEP

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Cystic fibrosis (CF) is a life-shortening monogenic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein, an anion channel that transports chloride and bicarbonate across epithelia. Despite clinical progress in delaying disease progression with symptomatic therapies, these individuals still develop various chronic complications in lungs and other organs, which significantly restricts their life expectancy and quality of life. The development of high-throughput assays to screen drug-like compound libraries have enabled the discovery of highly effective CFTR modulator therapies. These novel therapies target the primary defect underlying CF and are now approved for clinical use for individuals with specific CF genotypes. However, the clinically approved modulators only partially reverse CFTR dysfunction and there is still a considerable number of individuals with CF carrying rare CFTR mutations who remain without any effective CFTR modulator therapy. Accordingly, additional efforts have been pursued to identify novel and more potent CFTR modulators that may benefit a larger CF population. The use of ex vivo individual-derived specimens has also become a powerful tool to evaluate novel drugs and predict their effectiveness in a personalized medicine approach. In addition to CFTR modulators, pro-drugs aiming at modulating alternative ion channels/transporters are under development to compensate for the lack of CFTR function. These therapies may restore normal mucociliary clearance through a mutation-agnostic approach (ie, independent of CFTR mutation) and include inhibitors of the epithelial sodium channel (ENaC), modulators of the calcium-activated channel transmembrane 16A (TMEM16, or anoctamin 1) or of the solute carrier family 26A member 9 (SLC26A9), and anionophores. The present review focuses on recent progress and challenges for the development of ion channel/transporter-modulating drugs for the treatment of CF.

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Combination of Selective PARP3 and PARP16 Inhibitory Analogues of Latonduine A Corrects F508del-CFTR Trafficking

Cited by 12 publications

References 42 publications

Medicinal Chemistry Perspective on Targeting Mono-ADP-Ribosylating PARPs with Small Molecules

Medicinal Chemistry Perspective on Targeting Mono-ADP-Ribosylating PARPs with Small Molecules

Proteostasis Regulators in Cystic Fibrosis: Current Development and Future Perspectives

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

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