1-BENZYLSPIRO[PIPERIDINE-4,1′-PYRIDO[3,4-b]indole] ‘co-potentiators’ for minimal function CFTR mutants

Son, Jung‐Ho; Phuan, Puay‐Wah; Zhu, Jie; Lipman, Soren; Cheung, Amy; Tsui, Ka Yi; Tantillo, Dean J.; Haggie, Peter M.; Kurth, Mark J.

doi:10.1016/j.ejmech.2020.112888

Cited by 7 publications

(3 citation statements)

References 34 publications

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“…Using 2D HIO from 2 pwCF homozygous for N1303K, we observed a rescue response to treatment with ELEXA/TEZA/IVA as shown previously in HNE cultures (Laselva et al, 2021). In addition, and in agreement with previous studies, we showed a moderate rescue effect with the combined treatment of dual CFTR modulator treatment with ELEXA and IVA reaching a similar level of CFTR functional response compared with triple combination therapy (Phuan et al, 2019;Son et al, 2021;Ensinck et al, 2022). Using a reversed sequence of modulator application (IVA and ELEXA) in 2D HIO, this synergistic effect is shown to be interdependent between ELEXA and IVA and is not mainly driven by IVA as previously believed (Laselva et al, 2021).…”

Section: Discussionsupporting

confidence: 91%

Validating organoid-derived human intestinal monolayers for personalized therapy in cystic fibrosis

Birimberg-Schwartz

Bartlett

et al. 2023

Life Sci. Alliance

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Highly effective drugs modulating the defective protein encoded by the CFTR gene have revolutionized cystic fibrosis (CF) therapy. Preclinical drug-testing on human nasal epithelial (HNE) cell cultures and 3-dimensional human intestinal organoids (3D HIO) are used to address patient-specific variation in drug response and to optimize individual treatment for people with CF. This study is the first to report comparable CFTR functional responses to CFTR modulator treatment among patients with different classes of CFTR gene variants using the three methods of 2D HIO, 3D HIO, and HNE. Furthermore, 2D HIO showed good correlation to clinical outcome markers. A larger measurable CFTR functional range and access to the apical membrane were identified as advantages of 2D HIO over HNE and 3D HIO, respectively. Our study thus expands the utility of 2D intestinal monolayers as a preclinical drug testing tool for CF.

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Section: Discussionsupporting

confidence: 91%

Validating organoid-derived human intestinal monolayers for personalized therapy in cystic fibrosis

Birimberg-Schwartz

Bartlett

et al. 2023

Life Sci. Alliance

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“… 99 A spiro[piperidine-4,1-pyrido[3,4-b]indole compound demonstrated potentiation activity for N1303K and I1234-R1239del CFTR with additive effects when in combination with VX-770. 100 ASP-11 is an arylsulfonamide-pyrrolopyridine co-potentiator that acts synergistically with VX-770 in the rescue of F508del-, G551D-, N1303K- and W1282X-CFTR mutations in cell lines. 101 The effects of ASP-11 were confirmed for N1303K in HBE cells, but not for W1282X.…”

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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“…Tetrahydro-β-carbolines moieties exist in a wide variety of drugs and natural products and exhibit a wide spectrum of biological activities, such as anti -tumor, anti -Alzheimer, anti -HIV, and so on . Examples include the marketed drug Tadalafil, pharmaceutical agent AZD-9496 in clinical research and a series of compounds reported with potential antitumor activity, as well as the natural product Komavine (Figure ).…”

mentioning

confidence: 99%

Metal-Free Access to (Spirocyclic)Tetrahydro-β-carbolines in Water Using an Ion-Pair as a Superacidic Precatalyst

Zhang

Liu

et al. 2022

ACS Catal.

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The unprecedented triarylcarbonium ion-pair-catalyzed Pictet–Spengler reaction of tryptamines with aromatic aldehydes and cyclic ketones in water was disclosed. Under metal-free conditions, diverse tetrahydro-β-carbolines and spirocyclic tetrahydro-β-carbolines were obtained in good yields with excellent functional group tolerance, including late-stage modification of natural products and small molecular drugs. The practicability of this protocol is also characterized in the gram-scale synthesis of Komavine and several other functional compounds. Preliminary mechanistic studies indicated that in aqueous media the in situ-generated superacidic species from the carbonium ion pair with water was crucial to promote the Pictet–Spengler reaction.

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1-BENZYLSPIRO[PIPERIDINE-4,1′-PYRIDO[3,4-b]indole] ‘co-potentiators’ for minimal function CFTR mutants

Cited by 7 publications

References 34 publications

Validating organoid-derived human intestinal monolayers for personalized therapy in cystic fibrosis

Validating organoid-derived human intestinal monolayers for personalized therapy in cystic fibrosis

Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis

Metal-Free Access to (Spirocyclic)Tetrahydro-β-carbolines in Water Using an Ion-Pair as a Superacidic Precatalyst

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