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

Jun, Joonhong; Yang, Songyi; Lee, Jung-Hun; Moon, Hyungwoo; Kim, Jinwoong; Jung, Hoyong; Im, Daseul; Oh, Youri; Jang, Miyoung; Cho, Hyunwook; Baek, Jihyun; Kim, Hye-Jin; Kang, Dahyun; Bae, Hyunah; Tak, Chanwool; Hwang, Kyungrim; Kwon, Ho-Seok; Kim, HyunTae; Hah, Jung‐Mi

doi:10.1016/j.ejmech.2022.114894

Cited by 14 publications

(23 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The proposed binding mode of JNK1 in complex with 25c showed that due to the presence of an upward gatekeeper residue Met108 side chain, the interactions between 25c and the hydrophobic pocket I of JNK1 were blocked (Figure B ). Moreover, the same phenomenon was discovered in the Met108 residue from all PDB structures of JNK1, which may have collisions with the functional moiety of other JNK3 inhibitors . Likewise, we noticed that 25c was also not bound to the hydrophobic pocket I of JNK2 (PDB code: 3E7O) due to the presence of an upward Met108 side chain in JNK2.…”

Section: Resultssupporting

confidence: 70%

“…However, there are still optimizational spaces in hydrophobic pockets I and II. Previous studies have reported that some interactions between ligands with Lys93 in hydrophobic pocket I and some key residues in the solvent-exposed region also played key roles in improving the isoform selectivity and inhibitory activity for JNK3. − It was suggested that more functional groups could be introduced to the structure of hit 9 , especially for A and C regions, to increase key interactions.…”

Section: Resultsmentioning

confidence: 99%

“…Meanwhile, its therapeutic potency was demonstrated in two different AD models. However, poor brain penetration (brain: plasma = 0.02) may block its development as an AD candidate drug . Unfortunately, no isoform-selective JNK3 inhibitor has been used for the treatment and mechanism research of PD.…”

Section: Introductionmentioning

confidence: 99%

“…However, poor brain penetration (brain: plasma = 0.02) may block its development as an AD candidate drug. 26 Unfortunately, no isoform-selective JNK3 inhibitor has been used for the treatment and mechanism research of PD. In fact, few JNK inhibitors have been reported for PD treatment and research, except for some pan-JNK inhibitors, e.g., SP600125 and SR-3306.…”

Section: Introductionmentioning

confidence: 99%

“…However, there are no further studies on SR-3306 against PD. Recent studies have found that SR-3306 showed no neuroprotective effect on the amyloid-β-induced in vitro models of AD . With considerable efforts of some academic groups, JNK3 inhibitors with selectivity profiles have also been identified.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Discovery of Novel Indazole Chemotypes as Isoform-Selective JNK3 Inhibitors for the Treatment of Parkinson’s Disease

Wen

Zhu

et al. 2023

J. Med. Chem.

View full text Add to dashboard Cite

c-Jun N-terminal kinases (JNKs) are involved in the pathogenesis of various diseases. In particular, JNK3 and not JNK1/2 is primarily expressed in the brain and plays a key role in mediating neurodegenerative diseases like Parkinson's disease (PD). Due to the sequence similarity of JNK isoforms, developing isoform-selective JNK3 inhibitors to evaluate their biological functions and therapeutic potential in PD has become a challenge. Herein, docking-based virtual screening and structure−activity relationship studies identified 25c with excellent inhibitory activity against JNK3 (IC 50 = 85.21 nM) and exhibited an over 100-fold isoform selectivity for JNK3 over JNK1/2 and remarkable kinase selectivity. 25c showed neuroprotective effects on in vitro and in vivo PD models by selectively inhibiting JNK3. Meanwhile, 25c showed an ideal blood−brain barrier permeability and low toxicity. Overall, this study provided a valuable molecular tool for investigating the role of JNK3 in PD and a solid foundation for developing JNK3-targeted drugs in PD treatment.

show abstract

Section: Resultssupporting

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Discovery of Novel Indazole Chemotypes as Isoform-Selective JNK3 Inhibitors for the Treatment of Parkinson’s Disease

Wen

Zhu

et al. 2023

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

Targeting protein kinases for the treatment of Alzheimer's disease: Recent progress and future perspectives

Li,

Yin,

Zhang

et al. 2023

European Journal of Medicinal Chemistry

View full text Add to dashboard Cite

Carbamate JNK3 Inhibitors Show Promise as Effective Treatments for Alzheimer’s Disease: In Vivo Studies on Mouse Models

et al. 2023

Self Cite

View full text Add to dashboard Cite

We have been developing new inhibitors for c-Jun N-terminal kinase 3 (JNK3) as a potential treatment for Alzheimer’s disease (AD). We identified potential JNK3 inhibitors through pharmacodynamic optimization studies, including benzimidazole compounds 2 and 3, but their unreliable pharmacokinetic properties led us to develop carbamate inhibitors 2h and 3h. In vitro studies validated carbamate inhibitors 2h and 3h as potent and highly selective JNK3 inhibitors with favorable pharmacokinetic profiles. Oral administration of 2h and 3h to both APP/PS1 and 3xTg AD mouse models improved cognitive function, indicating their potential as effective treatments for Alzheimer’s disease. Carbamate JNK3 inhibitor 3h, in particular, restored cognitive function to near-normal levels in the 3xTg mice model of AD and led to pTau reduction in the hippocampal tissues of 3xTg-AD mice during in vivo behavioral evaluations. We intend to further develop these carbamate JNK3 inhibitors in preclinical studies as a potential first-in-class treatment for AD.

show abstract

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

Cited by 14 publications

References 37 publications

Discovery of Novel Indazole Chemotypes as Isoform-Selective JNK3 Inhibitors for the Treatment of Parkinson’s Disease

Discovery of Novel Indazole Chemotypes as Isoform-Selective JNK3 Inhibitors for the Treatment of Parkinson’s Disease

Targeting protein kinases for the treatment of Alzheimer's disease: Recent progress and future perspectives

Carbamate JNK3 Inhibitors Show Promise as Effective Treatments for Alzheimer’s Disease: In Vivo Studies on Mouse Models

Contact Info

Product

Resources

About