Discovery of Novel Chromenopyridine Derivatives as Readthrough-Inducing Drugs

Shota Kawai; Shunsuke Takashima; Masafumi Ando; Sayaka Shintaku; Shigemitsu Takeda; Kazuya Otake; Yuma Ito; Masaki Fukui; Megumi Yamamoto; Yoshimichi Shoji; Hiroaki Shirahase; Tatsuya Kitao

doi:10.1248/cpb.c23-00488

Regular Articles

Discovery of Novel Chromenopyridine Derivatives as Readthrough-Inducing Drugs

Shota Kawai , Shunsuke Takashima, Masafumi Ando, Sayaka Shintaku, Shigemitsu Takeda, Kazuya Otake, Yuma Ito, Masaki Fukui, Megumi Yamamoto, Yoshimichi Shoji, Hiroaki Shirahase, Tatsuya Kitao

Author information

Shota Kawai Corresponding author
Drug Discovery Research Department, Kyoto Pharmaceutical Industries, Ltd.
Shunsuke Takashima
Drug Discovery Research Department, Kyoto Pharmaceutical Industries, Ltd.
Masafumi Ando
Drug Discovery Research Department, Kyoto Pharmaceutical Industries, Ltd.
Sayaka Shintaku
Drug Discovery Research Department, Kyoto Pharmaceutical Industries, Ltd.
Shigemitsu Takeda
Drug Discovery Research Department, Kyoto Pharmaceutical Industries, Ltd.
Kazuya Otake
Drug Discovery Research Department, Kyoto Pharmaceutical Industries, Ltd.
Yuma Ito
Drug Discovery Research Department, Kyoto Pharmaceutical Industries, Ltd.
Masaki Fukui
Drug Discovery Research Department, Kyoto Pharmaceutical Industries, Ltd.
Megumi Yamamoto
Drug Discovery Research Department, Kyoto Pharmaceutical Industries, Ltd.
Yoshimichi Shoji
Drug Discovery Research Department, Kyoto Pharmaceutical Industries, Ltd.
Hiroaki Shirahase
Drug Discovery Research Department, Kyoto Pharmaceutical Industries, Ltd.
Tatsuya Kitao
Drug Discovery Research Department, Kyoto Pharmaceutical Industries, Ltd.

Keywords: readthrough, nonsense mutation, premature termination codon, mucopolysaccharidosis I-Hurler, lysosomal storage disease

JOURNAL FREE ACCESS FULL-TEXT HTML

2023 Volume 71 Issue 12 Pages 859-878

DOI https://doi.org/10.1248/cpb.c23-00488

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Abstract

Hurler syndrome, a type of Mucopolysaccharidosis type I, is an inherited disorder caused by the accumulation of glycosaminoglycans (GAG) due to a deficiency in lysosomal α-L-iduronidase (IDUA), resulting in multiorgan dysfunction. In many patients with Hurler syndrome, IDUA proteins are not produced due to nonsense mutations in their genes; therefore, readthrough-inducing compounds, such as gentamycin, are expected to restore IDUA proteins by skipping the premature termination codon. In the present study, we synthesized a series of chromenopyridine derivatives to identify novel readthrough-inducing compounds. The readthrough-inducing activities of synthesized compounds were examined by measuring cellular IDUA activities and GAG concentrations in Hurler syndrome patient-derived cells. Compounds with a difluorophenyl group at the 2-position of chromenopyridine, a cyclobutyl group at the 3-position, and a basic side chain or basic fused ring exhibited excellent readthrough-inducing activities. KY-640, a chromenopyridine derivative with a tetrahydroisoquinoline sub-structure, increased the cellular IDUA activities of patient-derived cells by 3.2-fold at 0.3 µM and significantly reduced GAG concentrations, and also significantly increased enzyme activity in mouse models, suggesting its therapeutic potential in patients with Hurler syndrome.

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