Recent Progress in the Discovery and Development of Small-Molecule Modulators of CFTR

Kym, Philip R.; Wang, Xueqing; Pizzonero, Mathieu; Plas, Steven E Van der

doi:10.1016/bs.pmch.2018.01.001

Cited by 29 publications

(25 citation statements)

References 69 publications

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“…Vertex has also completed clinical trials of VX-440 and VX-152 in combination with tezacaftor/ivacaftor, but pursued elexacaftor as the third element of their triple-combination strategy [169]. Additional correctors in clinical trials have been reported by Vertex, AbbVie, Flatley Discovery Lab, and Proteostasis Therapeutics (Table 1) [170,171].…”

Section: Cftr Correctorsmentioning

confidence: 99%

Transcriptomic and Proteostasis Networks of CFTR and the Development of Small Molecule Modulators for the Treatment of Cystic Fibrosis Lung Disease

Strub

McCray

2020

Genes

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Cystic fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The diversity of mutations and the multiple ways by which the protein is affected present challenges for therapeutic development. The observation that the Phe508del-CFTR mutant protein is temperature sensitive provided proof of principle that mutant CFTR could escape proteosomal degradation and retain partial function. Several specific protein interactors and quality control checkpoints encountered by CFTR during its proteostasis have been investigated for therapeutic purposes, but remain incompletely understood. Furthermore, pharmacological manipulation of many CFTR interactors has not been thoroughly investigated for the rescue of Phe508del-CFTR. However, high-throughput screening technologies helped identify several small molecule modulators that rescue CFTR from proteosomal degradation and restore partial function to the protein. Here, we discuss the current state of CFTR transcriptomic and biogenesis research and small molecule therapy development. We also review recent progress in CFTR proteostasis modulators and discuss how such treatments could complement current FDA-approved small molecules.

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Section: Cftr Correctorsmentioning

confidence: 99%

Transcriptomic and Proteostasis Networks of CFTR and the Development of Small Molecule Modulators for the Treatment of Cystic Fibrosis Lung Disease

Strub

McCray

2020

Genes

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“…The corrector/potentiator combinations Orkambi (VX-770 plus lumacaftor/VX-809) and Symdeko (VX-770 plus tezacaftor/VX-661) have been approved for CF subjects that are homozygous for the most common CF-causing CFTR mutation, F508del, or who have one F508del allele and a residual function CFTR mutation 2 . Trikafta, a triple drug combination consisting of two correctors and one potentiator, has recently been approved for CF subjects with one or two F508del alleles 2,4–6 . Trikafta and future CFTR modulators may benefit up to 90% of CF subjects 2 .…”

Section: Introductionmentioning

confidence: 99%

Nanomolar-potency ‘co-potentiator’ therapy for cystic fibrosis caused by a defined subset of minimal function CFTR mutants

Phuan

Tan

Rivera

et al. 2019

Sci Rep

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Available CFTR modulators provide no therapeutic benefit for cystic fibrosis (CF) caused by many lossof-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, including N1303K. We previously introduced the concept of 'co-potentiators' (combinationpotentiators) to rescue CFTR function in some minimal function CFTR mutants. Herein, a screen of ~120,000 drug-like synthetic small molecules identified active co-potentiators of pyrazoloquinoline, piperidine-pyridoindole, tetrahydroquinoline and phenylazepine classes, with EC 50 down to ~300 nM following initial structure-activity studies. Increased CFTR chloride conductance by up to 8-fold was observed when a co-potentiator (termed 'Class II potentiator') was used with a classical potentiator ('Class I potentiator') such as VX-770 or GLPG1837. To investigate the range of CFTR mutations benefitted by co-potentiators, 14 CF-associated CFTR mutations were studied in transfected cell models. Co-potentiator efficacy was found for CFTR missense, deletion and nonsense mutations in nucleotide binding domain-2 (NBD2), including W1282X, N1303K, c.3700A > G and Q1313X (with corrector for some mutations). In contrast, CFTR mutations G85E, R334W, R347P, V520F, R560T, A561E, M1101K and R1162X showed no co-potentiator activity, even with corrector. Co-potentiator efficacy was confirmed in primary human bronchial epithelial cell cultures generated from a N1303K homozygous CF subject. The Class II potentiators identified here may have clinical benefit for CF caused by mutations in the NBD2 domain of CFTR. Cystic fibrosis (CF) is caused by loss of function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a cAMP-activated chloride channel 1. More than 2000 CF-causing CFTR variants have been identified (http://genet.sickkids.on.ca/Home.html). CFTR modulators have been developed that rescue defective cellular processing and cell-surface targeting of mutant CFTRs (correctors) and defective channel gating (potentiators) to restore CFTR anion transport 1-3. The potentiator Kalydeco (ivacaftor/VX-770) has been approved for CF subjects with gating mutations, including G551D-CFTR and now 38 additional mutations 2. The corrector/potentiator combinations Orkambi (VX-770 plus lumacaftor/VX-809) and Symdeko (VX-770 plus tezacaftor/VX-661) have been approved for CF subjects that are homozygous for the most common CF-causing CFTR mutation, F508del, or who have one F508del allele and a residual function CFTR mutation 2. Trikafta, a triple drug combination consisting of two correctors and one potentiator, has recently been approved for CF subjects with one or two F508del alleles 2,4-6. Trikafta and future CFTR modulators may benefit up to 90% of CF subjects 2. Therapeutic approaches are needed for CFTR mutations that are unlikely to benefit from existing modulators-the so-called 'remaining 10%' 2,7,8. Non-responsive minimal function CFTR mutations are distributed throughout the CFTR protein and are associated with low CF...

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“…While over 1700 individual CFTR variants have been identified, CFTR variants are grouped by pathogenesis mechanisms including absence of mature protein (nonsense, frameshift variants), disruption of intracellular trafficking to the epithelial cell surface, and impaired chloride transport (https://www.cftr2.org). 53 Functional characterization of CFTR variants and high‐throughput screening of small‐molecule compounds have led to personalized therapies (eg, VX‐770, VX‐661, VX‐809, VX‐445) based on CFTR genotype, 1‐3,54‐57 with combination drugs that can now treat approximately 90% of CF patients, and can serve as a paradigm for understanding and treating other monogenic lung diseases.…”

Section: New Approaches To Identify Molecular Mechanisms and Therapeumentioning

confidence: 99%

Childhood rare lung disease in the 21st century: “‐omics” technology advances accelerating discovery

Vece

Wambach

Hagood

2020

Pediatric Pulmonology

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Childhood rare lung diseases comprise a large number of heterogeneous respiratory disorders that are individually rare but are collectively associated with substantial morbidity, mortality, and healthcare resource utilization. Although the genetic mechanisms for several of these disorders have been elucidated, the pathogenesis mechanisms for others remain poorly understood and treatment options remain limited. Childhood rare lung diseases are enriched for genetic etiologies; identification of the disease mechanisms underlying these rare disorders can inform the biology of normal human lung development and has implications for the treatment of more common respiratory diseases in children and adults. Advances in "-omics" technology, such as genomic sequencing, clinical phenotyping, biomarker discovery, genome editing, in vitro and model organism disease modeling, single-cell analyses, cellular imaging, and high-throughput drug screening have enabled significant progress for diagnosis and treatment of rare childhood lung diseases. The most striking example of this progress has been realized for patients with cystic fibrosis for whom effective, personalized therapies based on CFTR genotype are now available. In this chapter, we focus on recent technology advances in childhood rare lung diseases, acknowledge persistent challenges, and identify promising new technologies that will impact not only biological discovery, but also improve diagnosis, therapies, and survival for children with these rare disorders.

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Recent Progress in the Discovery and Development of Small-Molecule Modulators of CFTR

Cited by 29 publications

References 69 publications

Transcriptomic and Proteostasis Networks of CFTR and the Development of Small Molecule Modulators for the Treatment of Cystic Fibrosis Lung Disease

Transcriptomic and Proteostasis Networks of CFTR and the Development of Small Molecule Modulators for the Treatment of Cystic Fibrosis Lung Disease

Nanomolar-potency ‘co-potentiator’ therapy for cystic fibrosis caused by a defined subset of minimal function CFTR mutants

Childhood rare lung disease in the 21st century: “‐omics” technology advances accelerating discovery

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