The discovery of 3,3-dimethyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamides as AMPD2 inhibitors with a novel mechanism of action

Kitao, Yuki; Saito, T.; Watanabe, Satoshi; Ohe, Yasuhiro; Takahashi, Kyoko; Akaki, Tatsuo; Adachi, Tsuyoshi; Doi, Satoki; Yamanaka, Kazushi; Murai, Yuriko; Oba, Makoto; Suzuki, Takayoshi

doi:10.1016/j.bmcl.2022.129110

Cited by 3 publications

(1 citation statement)

References 12 publications

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“…AMPD2 plays an important role in energy homeostasis [59], as it is involved in the metabolism of purine nucleotides, resulting in the generation of ATP and GTP which are critical for production and synthesis of nucleic acids [60]. De novo purine synthesis begins with the conversion of ribose-5-phosphate to IMP, which is then converted to ATP or GTP, based on cellular requirements [57].…”

Section: Discussionmentioning

confidence: 99%

Frameshift Variant in AMPD2 in Cirneco dell’Etna Dogs with Retinopathy and Tremors

Murgiano,

Niggel,

Benedicenti

et al. 2024

Genes

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While the manifestations of many inherited retinal disorders are limited to loss of vision, others are part of a syndrome that affects multiple tissues, particularly the nervous system. Most syndromic retinal disorders are thought to be recessively inherited. Two dogs out of a litter of Cirneco dell′ Etna dogs, both males, showed signs of retinal degeneration, along with tremors and signs described as either atypical seizures or paroxysmal dyskinesias, while the other two male littermates were normal. We named this oculo-neurological syndrome CONS (Cirneco oculo-neurological syndrome), and undertook homozygosity mapping and whole-genome sequencing to determine its potential genetic etiology. Notably, we detected a 1-bp deletion in chromosome 6 that was predicted to cause a frameshift and premature stop codon within the canine AMPD2 gene, which encodes adenosine monophosphate deaminase, an enzyme that converts adenosine 5′-monophosphate (AMP) to inosine 5’-monophosphate (IMP). Genotyping of the available Cirneco population suggested perfect segregation between cases and controls for the variant. Moreover, this variant was absent in canine genomic databases comprised of thousands of unaffected dogs. The AMPD2 genetic variant we identified in dogs presents with retinal manifestations, adding to the spectrum of neurological manifestations associated with AMPD2 variants in humans.

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Section: Discussionmentioning

confidence: 99%

Frameshift Variant in AMPD2 in Cirneco dell’Etna Dogs with Retinopathy and Tremors

Murgiano,

Niggel,

Benedicenti

et al. 2024

Genes

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A drug-mediated organic electrochemical transistor for robustly reusable biosensors

Jiang,

Ye,

Xiang

et al. 2024

Nat. Mater.

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Broadening the phenotype and genotype spectrum of novel mutations in pontocerebellar hypoplasia with a comprehensive molecular literature review

Ghasemi,

Tehrani Fateh,

Moeinafshar

et al. 2024

BMC Med Genomics

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Background Pontocerebellar hypoplasia is an umbrella term describing a heterogeneous group of prenatal neurodegenerative disorders mostly affecting the pons and cerebellum, with 17 types associated with 25 genes. However, some types of PCH lack sufficient information, which highlights the importance of investigating and introducing more cases to further elucidate the clinical, radiological, and biochemical features of these disorders. The aim of this study is to provide an in-depth review of PCH and to identify disease genes and their inheritance patterns in 12 distinct Iranian families with clinically confirmed PCH. Methods Cases included in this study were selected based on their phenotypic and genetic information available at the Center for Comprehensive Genetic Services. Whole-exome sequencing (WES) was used to discover the underlying genetic etiology of participants' problems, and Sanger sequencing was utilized to confirm any suspected alterations. We also conducted a comprehensive molecular literature review to outline the genetic features of the various subtypes of PCH. Results This study classified and described the underlying etiology of PCH into three categories based on the genes involved. Twelve patients also were included, eleven of whom were from consanguineous parents. Ten different variations in 8 genes were found, all of which related to different types of PCH. Six novel variations were reported, including SEPSECS, TSEN2, TSEN54, AMPD2, TOE1, and CLP1. Almost all patients presented with developmental delay, hypotonia, seizure, and microcephaly being common features. Strabismus and elevation in lactate levels in MR spectroscopy were novel phenotypes for the first time in PCH types 7 and 9. Conclusions This study merges previously documented phenotypes and genotypes with unique novel ones. Due to the diversity in PCH, we provided guidance for detecting and diagnosing these heterogeneous groups of disorders. Moreover, since certain critical conditions, such as spinal muscular atrophy, can be a differential diagnosis, providing cases with novel variations and clinical findings could further expand the genetic and clinical spectrum of these diseases and help in better diagnosis. Therefore, six novel genetic variants and novel clinical and paraclinical findings have been reported for the first time. Further studies are needed to elucidate the underlying mechanisms and potential therapeutic targets for PCH.

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The discovery of 3,3-dimethyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamides as AMPD2 inhibitors with a novel mechanism of action

Cited by 3 publications

References 12 publications

Frameshift Variant in AMPD2 in Cirneco dell’Etna Dogs with Retinopathy and Tremors

Frameshift Variant in AMPD2 in Cirneco dell’Etna Dogs with Retinopathy and Tremors

A drug-mediated organic electrochemical transistor for robustly reusable biosensors

Broadening the phenotype and genotype spectrum of novel mutations in pontocerebellar hypoplasia with a comprehensive molecular literature review

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