Identification of α-Synuclein Proaggregator: Rapid Synthesis and Streamlining RT-QuIC Assays in Parkinson's Disease

Fumito Takada; Takahito Kasahara; Kentaro Otake; Takamitsu Maru; Masanori Miwa; Kei Muto; Minoru Sasaki; Yoshihiko Hirozane; Masato Yoshikawa; Junichiro Yamaguchi

doi:10.1021/acsmedchemlett.2c00138

Identification of α-Synuclein Proaggregator: Rapid Synthesis and Streamlining RT-QuIC Assays in Parkinson's Disease

ACS Med Chem Lett. 2022 Aug 11;13(9):1421-1426. doi: 10.1021/acsmedchemlett.2c00138. eCollection 2022 Sep 8.

Affiliations

¹ Department of Applied Chemistry, Waseda University, 513 Wasedatsurumakicho, Shinjuku, Tokyo 162-0041, Japan.
² Takeda Pharmaceutical Company Limited, 2-26-1 Muraoka-Higashi, Fujisawa, Kanagawa 251-8555, Japan.
³ Axcelead Drug Discovery Partners Inc., 2-26-1 Muraoka-Higashi, Fujisawa, Kanagawa 251-8555, Japan.
⁴ Waseda Institute for Advanced Study, Waseda University, 513 Wasedatsurumakicho, Shinjuku, Tokyo 162-0041, Japan.

Abstract

We report the discovery of two compounds, TKD150 and TKD152, that promote the aggregation of α-synuclein (aSN) using a real-time quaking-induced conversion (RT-QuIC) assay to detect abnormal aSN. By utilizing a Pd-catalyzed C-H arylation of benzoxazole with iodoarenes and implementing a planar conformation to the design, we successfully identified TKD150 and TKD152 as proaggregators for aSN. In comparison to a previously reported proaggregator, PA86, the two identified compounds were able to promote aggregation of aSN at twice the rate. Application of TKD150 and TKD152 to the RT-QuIC assay will shorten the inherent lag time and may allow wider use of this assay in clinical settings for the diagnosis of α-synucleinopathy-related diseases.