PTI-801 (posenacaftor) shares a common mechanism with VX-445 (elexacaftor) to rescue p.Phe508del-CFTR

Ferreira, Filipa C.; Amaral, Margarida D.; Bacalhau, Mafalda; Lopes-Pacheco, Miquéias

doi:10.1016/j.ejphar.2024.176390

Cited by 2 publications

(4 citation statements)

References 68 publications

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“…While this manuscript was under review, a new study was published and demonstrated that PTI-801 (posenacaftor)—a third-generation corrector—shares a common mechanism with elexacaftor to rescue p.Phe508del-CFTR [ 134 ]. By employing biochemical, fluorescence microscopy, and functional assays, PTI-801 has been demonstrated to rescue p.Phe508del-CFTR with greater correction effects in combination with type I correctors (tezacaftor, lumacaftor, ABBV-2222, or FDL-169), but not with elexacaftor.…”

Section: Elexacaftor (Vx-445) and Triple Combination With Tezacaftor ...mentioning

confidence: 99%

“…By employing biochemical, fluorescence microscopy, and functional assays, PTI-801 has been demonstrated to rescue p.Phe508del-CFTR with greater correction effects in combination with type I correctors (tezacaftor, lumacaftor, ABBV-2222, or FDL-169), but not with elexacaftor. PTI-801 and elexacaftor also displayed similar behavior on genetic revertants of p.Phe508del-CFTR (p.Val510Asp, p.GlyG550Glu, p.Arg1070Trp, and 4RK), and their rescue effects were abrogated in the in cis p.Arl1102Ala [ 134 ]. These findings suggest that PTI-801 can be a feasible alternative for the development of novel modulator combinations, aiming to attain greater rescue of CFTR variants.…”

Section: Elexacaftor (Vx-445) and Triple Combination With Tezacaftor ...mentioning

confidence: 99%

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Organic Synthesis and Current Understanding of the Mechanisms of CFTR Modulator Drugs Ivacaftor, Tezacaftor, and Elexacaftor

Ferreira,

Buarque,

Lopes-Pacheco

2024

Molecules

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The monogenic rare disease Cystic Fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance (CFTR) protein, an anion channel expressed at the apical plasma membrane of epithelial cells. The discovery and subsequent development of CFTR modulators—small molecules acting on the basic molecular defect in CF—have revolutionized the standard of care for people with CF (PwCF), thus drastically improving their clinical features, prognosis, and quality of life. Currently, four of these drugs are approved for clinical use: potentiator ivacaftor (VX-770) alone or in combination with correctors lumacaftor, (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). Noteworthily, the triple combinatorial therapy composed of ivacaftor, tezacaftor, and elexacaftor constitutes the most effective modulator therapy nowadays for the majority of PwCF. In this review, we exploit the organic synthesis of ivacaftor, tezacaftor, and elexacaftor by providing a retrosynthetic drug analysis for these CFTR modulators. Furthermore, we describe the current understanding of the mechanisms of action (MoA’s) of these compounds by discussing several studies that report the key findings on the molecular mechanisms underlying their action on the CFTR protein.

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Section: Elexacaftor (Vx-445) and Triple Combination With Tezacaftor ...mentioning

confidence: 99%

Section: Elexacaftor (Vx-445) and Triple Combination With Tezacaftor ...mentioning

confidence: 99%

Organic Synthesis and Current Understanding of the Mechanisms of CFTR Modulator Drugs Ivacaftor, Tezacaftor, and Elexacaftor

Ferreira,

Buarque,

Lopes-Pacheco

2024

Molecules

Self Cite

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“…This activity is enhanced when VX-661 and VX-809 is combined with PTI, but no such results were obtained when combined with VX-445. PTI and VX-445 are both correctors that act using same mechanism of action [ 62 ].…”

Section: Cftr Modulatorsmentioning

confidence: 99%

“…Subsequent research in children aged 6 to 11 revealed notable gains in lung function, but not in BMI or CFQ-R ratings; several unfavorable side-effects forced the trial’s termination. Although the effectiveness of the combination therapy is recognized, its usage is restricted due to concerns about drug interactions and safety [ 62 , 76 , 77 , 78 , 79 ].…”

Section: Monotherapy To Triple Combination Therapy (Eti)mentioning

confidence: 99%

Cystic Fibrosis: Understanding Cystic Fibrosis Transmembrane Regulator Mutation Classification and Modulator Therapies

Anwar,

Peng,

Zahid

et al. 2024

ARM

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A common life-threatening hereditary disease, Cystic Fibrosis (CF), affects primarily Caucasian infants. High sweat-salt levels are observed as a result of a single autosomal mutation in chromosome 7 that affects the critical function of the cystic fibrosis transmembrane regulator (CFTR). For establishing tailored treatment strategies, it is important to understand the broad range of CFTR mutations and their impacts on disease pathophysiology. This study thoroughly investigates the six main classes of classification of CFTR mutations based on their functional effects. Each class is distinguished by distinct molecular flaws, such as poor protein synthesis, misfolding, gating defects, conduction defects, and decreased CFTR expression at the apical membrane. Furthermore, this paper focuses on the emerging field of CFTR modulators, which intend to restore CFTR function or mitigate its consequences. These modulators, which are characterized by the mode of action and targeted mutation class, have the potential to provide personalized therapy regimens in CF patients. This review provides valuable insights into the genetic basis of CF pathology, and highlights the potential for precision medicine methods in CF therapy by thoroughly investigating CFTR mutation classification and related modulators.

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PTI-801 (posenacaftor) shares a common mechanism with VX-445 (elexacaftor) to rescue p.Phe508del-CFTR

Cited by 2 publications

References 68 publications

Organic Synthesis and Current Understanding of the Mechanisms of CFTR Modulator Drugs Ivacaftor, Tezacaftor, and Elexacaftor

Organic Synthesis and Current Understanding of the Mechanisms of CFTR Modulator Drugs Ivacaftor, Tezacaftor, and Elexacaftor

Cystic Fibrosis: Understanding Cystic Fibrosis Transmembrane Regulator Mutation Classification and Modulator Therapies

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