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Structural basis and biological consequences for JNK2/3 isoform selective aminopyrazoles.

Park H, Iqbal S, Hernandez P, Mora R, Zheng K, Feng Y, LoGrasso P
Sci Rep 5 8047 (2015)
Related entries: 4w4w, 4w4x, 4w4y

Cited: 12 times
EuropePMC logo PMID: 25623238

Abstract

Three JNK isoforms, JNK1, JNK2, and JNK3 have been reported and unique biological function has been ascribed to each. It is unknown if selective inhibition of these isoforms would confer therapeutic or safety benefit. To probe JNK isoform function we designed JNK2/3 inhibitors that have >30-fold selectivity over JNK1. Utilizing site-directed mutagenesis and x-ray crystallography we identified L144 in JNK3 as a key residue for selectivity. To test whether JNK2/3 selective inhibitors protect human dopaminergic neurons against neurotoxin-induced mitochondrial dysfunction, we monitored reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP). The results showed that JNK2/3 selective inhibitors protected against 6-hydroxydopamine-induced ROS generation and MMP depolarization. These results suggest that it was possible to develop JNK2/3 selective inhibitors and that residues in hydrophobic pocket I were responsible for selectivity. Moreover, the findings also suggest that inhibition of JNK2/3 likely contributed to protecting mitochondrial function and prevented ultimate cell death.

Reviews - 4w4v mentioned but not cited (1)

  1. C-Jun N-terminal kinase inhibitors: Structural insight into kinase-inhibitor complexes. Duong MTH, Lee JH, Ahn HC. Comput Struct Biotechnol J 18 1440-1457 (2020)

Articles - 4w4v mentioned but not cited (1)

  1. Structural basis and biological consequences for JNK2/3 isoform selective aminopyrazoles. Park H, Iqbal S, Hernandez P, Mora R, Zheng K, Feng Y, LoGrasso P. Sci Rep 5 8047 (2015)


Reviews citing this publication (2)

  1. c-Jun N-Terminal Kinase Inhibitors as Potential Leads for New Therapeutics for Alzheimer's Diseases. Hepp Rehfeldt SC, Majolo F, Goettert MI, Laufer S. Int J Mol Sci 21 E9677 (2020)
  2. A Perspective on the Development of c-Jun N-terminal Kinase Inhibitors as Therapeutics for Alzheimer's Disease: Investigating Structure through Docking Studies. Cho H, Hah JM. Biomedicines 9 1431 (2021)

Articles citing this publication (8)

  1. Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) Inhibitors. Zheng K, Park CM, Iqbal S, Hernandez P, Park H, LoGrasso PV, Feng Y. ACS Med Chem Lett 6 413-418 (2015)
  2. Thiophene-Pyrazolourea Derivatives as Potent, Orally Bioavailable, and Isoform-Selective JNK3 Inhibitors. Feng Y, Park H, Bauer L, Ryu JC, Yoon SO. ACS Med Chem Lett 12 24-29 (2021)
  3. c-Jun N-terminal kinases 3 (JNK3) from orange-spotted grouper, Epinephelus coioides, inhibiting the replication of Singapore grouper iridovirus (SGIV) and SGIV-induced apoptosis. Guo M, Wei J, Zhou Y, Qin Q. Dev Comp Immunol 65 169-181 (2016)
  4. N-Aromatic-Substituted Indazole Derivatives as Brain-Penetrant and Orally Bioavailable JNK3 Inhibitors. Feng Y, Park H, Ryu JC, Yoon SO. ACS Med Chem Lett 12 1546-1552 (2021)
  5. In vitro and in silico studies of 7'',8''-buddlenol D anti-inflammatory lignans from Carallia brachiata as p38 MAP kinase inhibitors. Nalinratana N, Suriya U, Laprasert C, Wisidsri N, Poldorn P, Rungrotmongkol T, Limpanasitthikul W, Wu HC, Chang HS, Chansriniyom C. Sci Rep 13 3558 (2023)
  6. Proposing the Promiscuous Protein Structures in JNK1 and JNK3 for Virtual Screening in Pursuit of Potential Leads. Sailapathi A, Murugan G, Somarathinam K, Gunalan S, Jagadeesan R, Yoosuf N, Kanagaraj S, Kothandan G. ACS Omega 5 3969-3978 (2020)
  7. Radiolabeled Aminopyrazoles as Novel Isoform Selective Probes for pJNK3 Quantification. Bales BC, Cotero V, Meyer DE, Roberts JC, Rodriguez-Silva M, Siclovan TM, Chambers JW, Rishel MJ. ACS Med Chem Lett 13 1606-1614 (2022)
  8. c-JUN n-Terminal Kinase (JNK) Signaling in Autosomal Dominant Polycystic Kidney Disease. Smith AO, Jonassen JA, Preval KM, Davis RJ, Pazour GJ. J Cell Signal 3 62-78 (2022)


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