Discovery of Icenticaftor (QBW251), a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator with Clinical Efficacy in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease

Grand, Darren Le; Gosling, Martin; Baettig, Urs; Bahra, Parmjit; Bala, Kamlesh; Brocklehurst, Cara E.; Budd, Emma; Butler, R. N.; Cheung, Atwood K.; Choudhury, Hedaythul; Collingwood, Stephen P.; Cox, Brian J.; Danahay, Henry; Edwards, Lee J.; Everatt, Brian; Glaenzel, Ulrike; Glotin, Anne-Lise; Groot-Kormelink, Paul J.; Hall, Edward J.; Hatto, Julia; Howsham, Catherine; Hughes, Glyn A; King, Anna; Koehler, Julia; Kulkarni, Swarupa G.; Lightfoot, Megan; Nicholls, Ian A.; Page, C. J.; Pergl-Wilson, Giles; Popa, M. Oana; Robinson, Richard; Rowlands, David J.; Sharp, Tom; Spendiff, Matthew; Stanley, Emily; Steward, Oliver; Taylor, Roger; Tranter, Pamela; Wagner, Trixie; Watson, H; Williams, Gareth; Wright, Penny; Young, Alice; Sandham, David A.

doi:10.1021/acs.jmedchem.1c00343

Cited by 25 publications

(14 citation statements)

References 47 publications

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“…Wild-type (wt) CFTR degradation has been linked to the development of chronic obstructive pulmonary disease (COPD) ( Patel et al. , 2020 ; Grand et al. , 2021 ).…”

Section: Introductionmentioning

confidence: 99%

A small-molecule inhibitor and degrader of the RNF5 ubiquitin ligase

Ruan

Liang

Yan

et al. 2022

MBoC

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RNF5 E3 ubiquitin ligase has multiple biological roles and has been linked to the development of severe diseases such as cystic fibrosis, acute myeloid leukemia, and certain viral infections, emphasizing the importance of discovering small molecule RNF5 modulators for research and drug development. The present study describes the synthesis of a new benzo[b]thiophene derivative, FX12 that acts as a selective small-molecule inhibitor and degrader of RNF5. We initially identified the previously reported STAT3 inhibitor, Stattic, as an inhibitor of dislocation of misfolded proteins from the endoplasmic reticulum (ER) lumen to the cytosol in ER-associated degradation. A concise structure-activity relationship campaign (SAR) around the Stattic chemotype led to the synthesis of FX12 that has diminished activity in inhibition of STAT3 activation and retains dislocation inhibitory activity. FX12 binds to RNF5 and inhibits its E3 activity in vitro as well as promotes proteasomal degradation of RNF5 in cells. RNF5 as a molecular target for FX12 was supported by the facts that FX12 requires RNF5 to inhibit dislocation and negatively regulates RNF5 function. Thus, this study developed a small molecule inhibitor and degrader of the RNF5 ubiquitin ligase, providing a chemical biology tool for RNF5 research and therapeutic development.

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“…Wild-type (wt) CFTR degradation has been linked to the development of chronic obstructive pulmonary disease (COPD) ( Patel et al. , 2020 ; Grand et al. , 2021 ).…”

Section: Introductionmentioning

confidence: 99%

A small-molecule inhibitor and degrader of the RNF5 ubiquitin ligase

Ruan

Liang

Yan

et al. 2022

MBoC

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“…The continued development of efficacious CFTR modulators requires a better understanding of the function of this channel. The modulators from Vertex, although highly efficacious, do not impact all patients with eligible CFTR genotypes, nor do they solve all of the problems in this multiple organ system disease or lead to long-term stabilization of lung function ( Flume et al, 2018 ; Gauthier et al, 2020 ; Guimbellot et al, 2017 ; Konstan et al, 2017 ; Li et al, 2019 ; McKinzie et al, 2017 ; Moheet et al, 2021 ; Patel et al, 2020 ; Phuan et al, 2018 ), revealing a need to continue to study CFTR to develop new therapies ( Davies et al, 2019 ; Grand et al, 2021 ; Veit et al, 2018 ). Understanding the nature of the stable open state may aid in the rational design of drugs that can lock mutant CFTR channels open, leading to increased Cl − secretion and amelioration of CF disease and potentially some forms of chronic obstructive pulmonary disease and other lung disorders ( Raju et al, 2016 ; Solomon et al, 2016a ; Solomon et al, 2016b ).…”

Section: Translational Relevance: Toward Therapeutic Development Acro...mentioning

confidence: 99%

The molecular evolution of function in the CFTR chloride channel

Infield

Strickland

Gaggar

et al. 2021

Journal of General Physiology

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The ATP-binding cassette (ABC) transporter superfamily includes many proteins of clinical relevance, with genes expressed in all domains of life. Although most members use the energy of ATP binding and hydrolysis to accomplish the active import or export of various substrates across membranes, the cystic fibrosis transmembrane conductance regulator (CFTR) is the only known animal ABC transporter that functions primarily as an ion channel. Defects in CFTR, which is closely related to ABCC subfamily members that bear function as bona fide transporters, underlie the lethal genetic disease cystic fibrosis. This article seeks to integrate structural, functional, and genomic data to begin to answer the critical question of how the function of CFTR evolved to exhibit regulated channel activity. We highlight several examples wherein preexisting features in ABCC transporters were functionally leveraged as is, or altered by molecular evolution, to ultimately support channel function. This includes features that may underlie (1) construction of an anionic channel pore from an anionic substrate transport pathway, (2) establishment and tuning of phosphoregulation, and (3) optimization of channel function by specialized ligand–channel interactions. We also discuss how divergence and conservation may help elucidate the pharmacology of important CFTR modulators.

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“…Icenticaftor (QBW251) is a CFTR potentiator molecule that can restore CFTR dysfunction in certain CF genotypes [77]. A study on the efficacy and safety of Icenticaftor in COPD patients was recently published [8].…”

Section: Icenticaftor and Copdmentioning

confidence: 99%

Dysfunction in the Cystic Fibrosis Transmembrane Regulator in Chronic Obstructive Pulmonary Disease as a Potential Target for Personalised Medicine

et al. 2021

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In recent years, numerous pathways were explored in the pathogenesis of COPD in the quest for new potential therapeutic targets for more personalised medical care. In this context, the study of the cystic fibrosis transmembrane conductance regulator (CFTR) began to gain importance, especially since the advent of the new CFTR modulators which had the potential to correct this protein’s dysfunction in COPD. The CFTR is an ion transporter that regulates the hydration and viscosity of mucous secretions in the airway. Therefore, its abnormal function favours the accumulation of thicker and more viscous secretions, reduces the periciliary layer and mucociliary clearance, and produces inflammation in the airway, as a consequence of a bronchial infection by both bacteria and viruses. Identifying CFTR dysfunction in the context of COPD pathogenesis is key to fully understanding its role in the complex pathophysiology of COPD and the potential of the different therapeutic approaches proposed to overcome this dysfunction. In particular, the potential of the rehydration of mucus and the role of antioxidants and phosphodiesterase inhibitors should be discussed. Additionally, the modulatory drugs which enhance or restore decreased levels of the protein CFTR were recently described. In particular, two CFTR potentiators, ivacaftor and icenticaftor, were explored in COPD. The present review updated the pathophysiology of the complex role of CFTR in COPD and the therapeutic options which could be explored.

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Discovery of Icenticaftor (QBW251), a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator with Clinical Efficacy in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease

Cited by 25 publications

References 47 publications

A small-molecule inhibitor and degrader of the RNF5 ubiquitin ligase

A small-molecule inhibitor and degrader of the RNF5 ubiquitin ligase

The molecular evolution of function in the CFTR chloride channel

Dysfunction in the Cystic Fibrosis Transmembrane Regulator in Chronic Obstructive Pulmonary Disease as a Potential Target for Personalised Medicine

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