2. Academic Validation
  3. Discovery of novel imidazole chemotypes as isoform-selective JNK3 inhibitors for the treatment of Alzheimer's disease

Discovery of novel imidazole chemotypes as isoform-selective JNK3 inhibitors for the treatment of Alzheimer's disease

  • Eur J Med Chem. 2023 Jan 5;245(Pt 1):114894. doi: 10.1016/j.ejmech.2022.114894.
Joonhong Jun 1,  Songyi Yang 1,  Junghun Lee 1,  Hyungwoo Moon 1,  Jinwoong Kim 1,  Hoyong Jung 1,  Daseul Im 1,  Youri Oh 1,  Miyoung Jang 1,  Hyunwook Cho 1,  Jihyun Baek 1,  Hyejin Kim 1,  Dahyun Kang 1,  Hyunah Bae 1,  Chanwool Tak 1,  Kyungrim Hwang 2,  Hoseok Kwon 2,  HyunTae Kim 2,  Jung-Mi Hah 3
Affiliations

Affiliations

  • 1 Department of Pharmacy & Institute of Pharmaceutical Science and Technology College of Pharmacy, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do, 15588, South Korea.
  • 2 Research Center, Samjin Pharm. Co. Ltd., 90, Magokjungang 10-ro, Gangseo-gu, Seoul, 07794, South Korea.
  • 3 Department of Pharmacy & Institute of Pharmaceutical Science and Technology College of Pharmacy, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do, 15588, South Korea. Electronic address: [email protected].
PMID: 36343411 DOI: 10.1016/j.ejmech.2022.114894
Abstract

Despite innumerable efforts to develop effective therapeutics, it is difficult to achieve breakthrough treatments for Alzheimer's disease (AD), and the main reason is probably the absence of a clear target. Here, we reveal c-Jun N-terminal kinase 3 (JNK3), a protein kinase explicitly expressed in the brain and involved in neuronal Apoptosis, with a view toward providing effective treatment for AD. For many years, we have worked on JNK3 inhibitors and have discovered 2-aryl-1-pyrimidinyl-1H-imidazole-5-yl acetonitrile-based JNK3 inhibitors with superb potency (IC50 < 1.0 nM) and excellent selectivity over other protein kinases including isoforms JNK1 (>300 fold) and JNK2 (∼10 fold). Based on in vitro biological activity and DMPK properties, the lead compounds were selected for further in vivo studies. We confirmed that repeat administration of JNK3 inhibitors improved cognitive memory in APP/PS1 and the 3xTg mouse model. Overall, our results show that JNK3 could be a potential target protein for AD.

Keywords

3xTg mouse; APP/PS1; Alzheimer's disease; Imidazole; JNK3; Neurodegenerative diseases.

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