2. Academic Validation
  3. Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer's disease mice

Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer's disease mice

  • Proc Natl Acad Sci U S A. 2022 Jan 18;119(3):e2115082119. doi: 10.1073/pnas.2115082119.
Min Hee Park 1 2,  Kang Ho Park 1 2,  Byung Jo Choi 1 3,  Wan Hui Han 1 2,  Hee Ji Yoon 1 2,  Hye Yoon Jung 1 2,  Jihoon Lee 4,  Im-Sook Song 4,  Dong Yu Lim 5,  Min-Koo Choi 5,  Yang-Ha Lee 6,  Cheol-Min Park 6,  Ming Wang 7,  Jihoon Jo 8 9,  Hee-Jin Kim 10,  Seung Hyun Kim 10,  Edward H Schuchman 11,  Hee Kyung Jin 12 3,  Jae-Sung Bae 12 2
Affiliations

Affiliations

  • 1 KNU Alzheimer's Disease Research Institute, Kyungpook National University, Daegu 41566, South Korea.
  • 2 Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, South Korea.
  • 3 Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, South Korea.
  • 4 BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, Vessel-Organ Interaction Research Center (VOICE), College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, South Korea.
  • 5 College of Pharmacy, Dankook University, Cheon-an 31116, South Korea.
  • 6 Department of Chemistry, Ulsan National Institute of Science and Technology, Ulsan 44919, South Korea.
  • 7 BioMedical Sciences Graduate Program, Chonnam National University, Hwasun 58128, South Korea.
  • 8 Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju 501-757, South Korea.
  • 9 Department of Neurology, Chonnam National University Medical School, Gwangju 501-757, South Korea.
  • 10 Department of Neurology, Hanyang University College of Medicine, Seoul 04763, South Korea.
  • 11 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
  • 12 KNU Alzheimer's Disease Research Institute, Kyungpook National University, Daegu 41566, South Korea; hkjin@knu.ac.kr jsbae@knu.ac.kr.
PMID: 35027452 DOI: 10.1073/pnas.2115082119
Abstract

Alzheimer's disease (AD) is characterized by complex, multifactorial neuropathology, suggesting that small molecules targeting multiple neuropathological factors are likely required to successfully impact clinical progression. Acid sphingomyelinase (ASM) activation has been recognized as an important contributor to these neuropathological features in AD, leading to the concept of using ASM inhibitors for the treatment of this disorder. Here we report the identification of KARI 201, a direct ASM inhibitor evaluated for AD treatment. KARI 201 exhibits highly selective inhibition effects on ASM, with excellent pharmacokinetic properties, especially with regard to brain distribution. Unexpectedly, we found another role of KARI 201 as a ghrelin receptor agonist, which also has therapeutic potential for AD treatment. This dual role of KARI 201 in neurons efficiently rescued neuropathological features in AD mice, including amyloid beta deposition, Autophagy dysfunction, neuroinflammation, synaptic loss, and decreased hippocampal neurogenesis and synaptic plasticity, leading to an improvement in memory function. Our data highlight the possibility of potential clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.

Keywords

ASM direct inhibitor; Alzheimer’s disease; GHSR1 alpha agonist; memory improvement; small compound.

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