Use of a High-Throughput Phenotypic Screening Strategy to Identify Amplifiers, a Novel Pharmacological Class of Small Molecules That Exhibit Functional Synergy with Potentiators and Correctors

Giuliano, Kenneth A.; Wachi, Shinichiro; Drew, Lawrence; Dukovski, Danijela; Green, Olivia; Bastos, C.M.; Cullen, Matthew D.; Hauck, Sheila I.; Tait, Bradley D.; Muñoz, Benito; Lee, Po‐Shun; Miller, John P.

doi:10.1177/2472555217729790

Cited by 69 publications

(58 citation statements)

References 37 publications

(65 reference statements)

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“…It was demonstrated to selectively increase the expression of immature CFTR protein carrying different mutations without eliciting alteration in the expression of cellular stress response genes (Giuliano et al, 2018). PTI-428 also enhanced the rescue of CFTR in F508del-and DI1234_R1239-expressing cells when coadministered with lumacaftor/ivacaftor (Molinski et al, 2017;Giuliano et al, 2018). Furthermore, the triple combination PTI-428/PTI-808/PTI-801 enhanced the CFTR-dependent chloride secretion to almost normal levels in F508del-expressing cells.…”

Section: Amplifiers: Increasing the Abundance Of Protein Substratementioning

confidence: 98%

“…The PTI-428 (nesolicaftor; Proteostasis Therapeutics) is the first-in-class amplifier investigated in clinical trials. It was demonstrated to selectively increase the expression of immature CFTR protein carrying different mutations without eliciting alteration in the expression of cellular stress response genes (Giuliano et al, 2018). PTI-428 also enhanced the rescue of CFTR in F508del-and DI1234_R1239-expressing cells when coadministered with lumacaftor/ivacaftor (Molinski et al, 2017;Giuliano et al, 2018).…”

Section: Amplifiers: Increasing the Abundance Of Protein Substratementioning

confidence: 99%

“…Numerous libraries of compounds have been screened by distinct high-throughput screening (HTS) methods and using several cell models. These experimental approaches have been contributing to the identification of small-molecules from different chemical series (Pedemonte et al, 2005a;Van Goor et al, 2009;Van Goor et al, 2011;Phuan et al, 2014;Phuan et al, 2015;Liang et al, 2017;Giuliano et al, 2018;Van der Plas et al, 2018;Veit et al, 2018;Wang et al, 2018;Berg et al, 2019;De Wilde et al, 2019;Merket et al, 2019) (Figure 6). Notably, as cell background may significantly influence the pharmacological rescue of CFTR mutants (Pedemonte et al, 2010), most promising hits should be further validated in well-differentiated cells in order to identify non-cytotoxic and effective compounds that might result in optimal therapeutic benefits in the clinical scenario.…”

Section: Cf-causing Mutations and Progress In Precision Medicinementioning

confidence: 99%

“…The 3849+10kbC>T, 2789+5G>A, and A455E are common mutations that cause such abnormalities (Class V, Figure 4) and are found in 0.8%, 0.7%, and 0.4% of the CF alleles, respectively (CFTR2 Database). Amplifiers are compounds that increase expression of CFTR mRNA and, consequently, biosynthesis of the CFTR protein (Giuliano et al, 2018).…”

Section: Amplifiers: Increasing the Abundance Of Protein Substratementioning

confidence: 99%

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CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

2020

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Cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which result in impairment of CFTR mRNA and protein expression, function, stability or a combination of these. Although CF leads to multifaceted clinical manifestations, the respiratory disorder represents the major cause of morbidity and mortality of these patients. The life expectancy of CF patients has substantially lengthened due to early diagnosis and improvements in symptomatic therapeutic regimens. Quality of life remains nevertheless limited, as these individuals are subjected to considerable clinical, psychosocial and economic burdens. Since the discovery of the CFTR gene in 1989, tremendous efforts have been made to develop therapies acting more upstream on the pathogenesis cascade, thereby overcoming the underlying dysfunctions caused by CFTR mutations. In this line, the advances in cell-based high-throughput screenings have been facilitating the fast-tracking of CFTR modulators. These modulator drugs have the ability to enhance or even restore the functional expression of specific CF-causing mutations, and they have been classified into five main groups depending on their effects on CFTR mutations: potentiators, correctors, stabilizers, read-through agents, and amplifiers. To date, four CFTR modulators have reached the market, and these pharmaceutical therapies are transforming patients' lives with short-and long-term improvements in clinical outcomes. Such breakthroughs have paved the way for the development of novel CFTR modulators, which are currently under experimental and clinical investigations. Furthermore, recent insights into the CFTR structure will be useful for the rational design of next-generation modulator drugs. This review aims to provide a summary of recent developments in CFTR-directed therapeutics. Barriers and future directions are also discussed in order to optimize treatment adherence, identify feasible and sustainable solutions for equitable access to these therapies, and continue to expand the pipeline of novel modulators that may result in effective precision medicine for all individuals with CF.

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Section: Amplifiers: Increasing the Abundance Of Protein Substratementioning

confidence: 98%

Section: Amplifiers: Increasing the Abundance Of Protein Substratementioning

confidence: 99%

Section: Cf-causing Mutations and Progress In Precision Medicinementioning

confidence: 99%

Section: Amplifiers: Increasing the Abundance Of Protein Substratementioning

confidence: 99%

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CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

2020

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“…Furthermore, the third type of modulator, which is still in development, is termed the amplifier. These modulators selectively promote cellular immature CFTR protein production, supplying correctors and potentiator with sufficient substrate (112). For instance, patients with CF and F508del mutations received gentamicin nasal drops for 14 days, which led to a 22% increase in their wild-type CFTR function (113).…”

Section: Clinical Applications Of Cf-associated Moleculesmentioning

confidence: 99%

Research advances in molecular mechanisms underlying the pathogenesis of cystic fibrosis: From technical improvement to clinical applications (Review)

Tao

Sui

et al. 2020

Mol Med Rep

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Cystic fibrosis (CF) is a chronic disease causing severe impairment to the respiratory system and digestive tracts. Currently, CF is incurable. As an autosomal recessive disorder, the morbidity of CF is significantly higher among Caucasians of European descent, whereas it is less pervasive among African and Asian populations. The disease is caused by identical mutations (homozygosity) or different mutations (heterozygosity) of an autosomal recessive mutation at position 7q31.2-q31.1 of chromosome 7. Diagnostic criteria and guidelines work concurrently with laboratory detection to facilitate precise CF detection. With technological advances, the understanding of CF pathogenesis has reached an unprecedented level, allowing for increasingly precise carrier screening, more effective early stage CF intervention and improved prognostic outcomes. These advances significantly increase the life quality and expectancy of patients with CF. Given the numerous improvements in the field of CF, the current review summarized the technical advances in the study of the molecular mechanisms underlying CF, as well as how these improvements facilitate the clinical outcomes of CF. Furthermore, challenges and obstacles to overcome are discussed.

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Rescue of common exon‐skipping mutations in cystic fibrosis with modified U1 snRNAs

et al. 2020

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Use of a High-Throughput Phenotypic Screening Strategy to Identify Amplifiers, a Novel Pharmacological Class of Small Molecules That Exhibit Functional Synergy with Potentiators and Correctors

Cited by 69 publications

References 37 publications

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

Research advances in molecular mechanisms underlying the pathogenesis of cystic fibrosis: From technical improvement to clinical applications (Review)

Rescue of common exon‐skipping mutations in cystic fibrosis with modified U1 snRNAs

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