Enthalpy-Driven Stabilization of Transthyretin by AG10 Mimics a Naturally Occurring Genetic Variant That Protects from Transthyretin Amyloidosis

Miller, Mark R.; Pal, Arindom; Albusairi, Wabel; Joo, Hyun; Pappas, Beverly; Tuhin, Md Tariqul Haque; Liang, De‐Yong; Jampala, Raghavendra; Liu, Fang; Khan, Jared; Faaij, Marjon; Park, Miki; Chan, William K.; Graef, Isabella A.; Zamboni, Robert; Kumar, Neil; Fox, Jonathan; Sinha, Uma; Alhamadsheh, Mamoun M.

doi:10.1021/acs.jmedchem.8b00817

Cited by 56 publications

(110 citation statements)

References 41 publications

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“…The Kd for the binding of a stabilizer to TTR is represented by the change in the Gibbs free energy of binding (ΔG), where ΔG = ΔH − TΔS. This technique has been used previously to compare small-molecule TTR stabilizers, like the small-molecule AG10 with other TTR tetramer stabilizer drugs [ 41 ].…”

Section: Resultsmentioning

confidence: 99%

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Repurposing Benzbromarone for Familial Amyloid Polyneuropathy: A New Transthyretin Tetramer Stabilizer

Cotrina¹,

Oliveira

Leite

et al. 2020

IJMS

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Transthyretin (TTR) is a homotetrameric protein involved in human amyloidosis, including familial amyloid polyneuropathy (FAP). Discovering small-molecule stabilizers of the TTR tetramer is a therapeutic strategy for these diseases. Tafamidis, the only approved drug for FAP treatment, is not effective for all patients. Herein, we discovered that benzbromarone (BBM), a uricosuric drug, is an effective TTR stabilizer and inhibitor against TTR amyloid fibril formation. BBM rendered TTR more resistant to urea denaturation, similarly to iododiflunisal (IDIF), a very potent TTR stabilizer. BBM competes with thyroxine for binding in the TTR central channel, with an IC50 similar to IDIF and tafamidis. Results obtained by isothermal titration calorimetry (ITC) demonstrated that BBM binds TTR with an affinity similar to IDIF, tolcapone and tafamidis, confirming BBM as a potent binder of TTR. The crystal structure of the BBM-TTR complex shows two molecules binding deeply in the thyroxine binding channel, forming strong intermonomer hydrogen bonds and increasing the stability of the TTR tetramer. Finally, kinetic analysis of the ability of BBM to inhibit TTR fibrillogenesis at acidic pH and comparison with other stabilizers revealed that benzbromarone is a potent inhibitor of TTR amyloidogenesis, adding a new interesting scaffold for drug design of TTR stabilizers.

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Section: Resultsmentioning

confidence: 99%

“…The Kd values reported in Table 1 were based on data fitted to an independent single-site binding model implemented in Origin 7.0 (OriginLab). Previous ITC studies for the binary complexes of tolcapone and tafamidis with TTR have used either a single model [ 42 ] or a two-site model to approximate binding to TTR [ 24 , 41 ].…”

Section: Resultsmentioning

confidence: 99%

Repurposing Benzbromarone for Familial Amyloid Polyneuropathy: A New Transthyretin Tetramer Stabilizer

Cotrina¹,

Oliveira

Leite

et al. 2020

IJMS

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“…14,26 When AG10 was co-crystallized with tetrameric TTR, this structure revealed that the two nitrogen atoms of AG10's pyrazole ring are similarly capable of forming hydrogen bonds with adjacent serine 117 residues. 14,28 These data suggest a structural basis to expect superior stabilizing properties of AG10 in vivo. No other stabilizer that binds to the thyroxine binding site, including TTR's natural ligand thyroxine, is structurally capable of similar molecular binding interactions.…”

Section: Discussionmentioning

confidence: 83%

“…Such hydrogen bonds can potentially explain the observed 40‐fold slower dissociation rate of the T119M tetramer as compared to the wild type tetramer . When AG10 was co‐crystallized with tetrameric TTR, this structure revealed that the two nitrogen atoms of AG10's pyrazole ring are similarly capable of forming hydrogen bonds with adjacent serine 117 residues . These data suggest a structural basis to expect superior stabilizing properties of AG10 in vivo.…”

Section: Discussionmentioning

confidence: 91%

First‐in‐Human Study of AG10, a Novel, Oral, Specific, Selective, and Potent Transthyretin Stabilizer for the Treatment of Transthyretin Amyloidosis: A Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study in Healthy Adult Volunteers

Fox

Hellawell

Rao

et al. 2019

Clinical Pharm in Drug Dev

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AG10 is a novel, potent, and selective oral transthyretin (TTR) stabilizer being developed to treat TTR amyloidosis (ATTR).This randomized,double-blind,placebo-controlled study evaluated safety,tolerability,pharmacokinetics,and pharmacodynamics (ex vivo stabilization) of orally administered AG10 in healthy adult volunteers. Both mutant and wild-type ATTR are underdiagnosed diseases with limited therapeutic options. As TTR amyloidogenesis is initiated by dissociation of TTR tetramers destabilized due to inherited mutations or aging, AG10 is designed to treat the disease at its source. Four single and three multiple ascending dose levels of AG10 or matching placebo were orally administered. Safety and tolerability were assessed by vital signs, electrocardiogram, adverse events, and clinical laboratory tests. Pharmacokinetics were measured using a validated bioanalytical assay. Pharmacodynamics were assessed via three pharmacodynamic assays of TTR stabilization. AG10 was uniformly well tolerated, and no safety signals of clinical concern were observed. Pharmacokinetic observations included time to maximum concentration <1 hour, dose-dependent maximum concentration and area under the plasma concentration-time curve, low intersubject variability, and half-life ß25 hr. Complete (>90%) stabilization of TTR was observed across the entire dosing interval at steady state on the highest dose tested. Serum TTR levels, an in vivo reflection of TTR stabilization by AG10, increased from baseline following 12 days of dosing. AG10 appears to be safe and well tolerated in healthy adult volunteers and can completely stabilize TTR across the dosing interval, establishing clinical proof of concept. Based on these data, AG10 has the potential to be a safe and effective treatment for patients with either mutant or wild-type ATTR.

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“…Other agents currently undergoing clinical development for the treatment of ATTRv include novel TTR stabilizers that offer greater stability of TTR tetramers (e.g. tolcapone [SOM0226], CSP-1103 [CHF5074], AG10) [34][35][36][37][38][39][40], combination therapy with doxycycline (disrupts TTR amyloid fibril formation) and tauroursodeoxycholic acid (reduces nonfibrillar TTR deposition) [41,42], and anti-TTR monoclonal antibodies that target amyloid monomers and inhibit fibril formation and promote phagocytosis of TTR aggregates [43][44][45]. While these agents show promise, published data from randomized controlled trials are currently lacking.…”

Section: Overview Of the Marketmentioning

confidence: 99%

Inotersen for the treatment of adults with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis

Gertz

Scheinberg

Waddington-Cruz

et al. 2019

Expert Review of Clinical Pharmacology

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Introduction: Hereditary transthyretin-mediated amyloidosis (ATTRv; v for variant) is an underdiagnosed, progressive, and fatal multisystemic disease with a heterogenous clinical phenotype that is caused by TTR gene mutations that destabilize the TTR protein, resulting in its misfolding, aggregation, and deposition in tissues throughout the body. Areas covered: Inotersen, an antisense oligonucleotide inhibitor, was recently approved in the United States and Europe for the treatment of the polyneuropathy of ATTRv based on the positive results obtained in the pivotal phase 3 trial, NEURO-TTR. This review will discuss the mechanism of action of inotersen and its pharmacology, clinical efficacy, and safety and tolerability. A PubMed search using the terms 'inotersen,' 'AG10,' 'antisense oligonucleotide,' 'hereditary transthyretin amyloidosis,' 'familial amyloid polyneuropathy,' and 'familial amyloid cardiomyopathy' was performed, and the results were screened for the most relevant English language publications. The bibliographies of all retrieved articles were manually searched to identify additional studies of relevance. Expert opinion: Inotersen targets the disease-forming protein, TTR, and has been shown to improve quality of life and neuropathy progression in patients with stage 1 or 2 ATTRv with polyneuropathy. Inotersen is well tolerated, with a manageable safety profile through regular monitoring for the development of glomerulonephritis or thrombocytopenia. ARTICLE HISTORYand wild-type TTR by targeting its mRNA. This article will review inotersen, an antisense oligonucleotide (ASO) inhibitor, for the treatment of polyneuropathy caused by ATTRv, focusing on the mechanism of action of inotersen and its pharmacology, clinical efficacy, and safety and tolerability.

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Enthalpy-Driven Stabilization of Transthyretin by AG10 Mimics a Naturally Occurring Genetic Variant That Protects from Transthyretin Amyloidosis

Cited by 56 publications

References 41 publications

Repurposing Benzbromarone for Familial Amyloid Polyneuropathy: A New Transthyretin Tetramer Stabilizer

Repurposing Benzbromarone for Familial Amyloid Polyneuropathy: A New Transthyretin Tetramer Stabilizer

First‐in‐Human Study of AG10, a Novel, Oral, Specific, Selective, and Potent Transthyretin Stabilizer for the Treatment of Transthyretin Amyloidosis: A Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study in Healthy Adult Volunteers

Inotersen for the treatment of adults with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis

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