2. Academic Validation
  3. Phenotypic screening of human iPSC-derived neurons identifies thienopyridones as neuritogenic small molecules

Phenotypic screening of human iPSC-derived neurons identifies thienopyridones as neuritogenic small molecules

  • iScience. 2026 Mar 30;29(5):115529. doi: 10.1016/j.isci.2026.115529.
Keiko Imamura 1 2 3 4,  Hiroshi Yukikate 2 5,  Takeshi Hioki 2 6,  Aya Okusa 1 4,  Keisuke Shibata 2 5,  Iñigo Narvaiza 2 6,  Akira Kaieda 7,  Bunnai Saito 7,  Nozomu Sakai 7,  Dang Ngoc Anh Suong 1 3,  Takeshi Niki 1 3,  Yuko Arioka 8,  Norio Ozaki 8,  Haruhisa Inoue 1 2 3 4
Affiliations

Affiliations

  • 1 Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
  • 2 Takeda-CiRA (T-CiRA) Joint Program, 2-26-1, Muraoka-Higashi, Fujisawa 251-8555, Japan.
  • 3 iPSC-based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), 1-7 Hikaridai, Seika-cho, Soraku-gun, Kyoto 619-0237, Japan.
  • 4 Medical-risk Avoidance Based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
  • 5 Global Advanced Platform, Takeda Pharmaceutical Company Limited, 2-26-1, Muraoka-Higashi, Fujisawa 251-8555, Japan.
  • 6 Neuroscience Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 2-26-1, Muraoka-Higashi, Fujisawa 251-8555, Japan.
  • 7 New Chemical Entity Production Laboratories, Takeda Pharmaceutical Company Limited, 2-26-1, Muraoka-Higashi, Fujisawa 251-8555, Japan.
  • 8 Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
PMID: 42028031 DOI: 10.1016/j.isci.2026.115529
Abstract

Human induced pluripotent stem cell (iPSC)-derived neurons provide a platform for modeling brain disorders. Among disease-relevant cellular phenotypes, impaired neurite outgrowth has emerged as an indicator reflecting key aspects of Neurological Disease pathophysiology. We conducted a high-throughput phenotypic screening of over 21,000 small molecules to identify compounds that enhance neurite outgrowth in iPSC-derived neurons, and we identified three bioactive compounds sharing a common indazole scaffold. Notably, one of these compounds selectively targets TNIK, a kinase involved in neuronal development. Scaffold expansion led to the discovery of thienopyridone derivatives with potent neurite-promoting activity. Two thienopyridone compounds were further validated in a human neural Organoid model, in which their neurite outgrowth-promoting effects were reproducibly confirmed. Transcriptomic profiling revealed activation of signaling pathways associated with neurotrophic stimulation. These findings identify thienopyridones as a scaffold for neuritogenic small molecules, suggesting their potential as a therapeutic strategy for brain disorders and for promoting neural regeneration.

Keywords

biological sciences; neuroscience; pharmacology; stem cells research.

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