4-Phenyl-7-azaindoles as potent, selective and bioavailable IKK2 inhibitors demonstrating good in vivo efficacy

Liddle, John; Bamborough, Paul; Barker, Michael D.; Campos, Sébastien; Chung, Chun‐wa; Cousins, Rick; Faulder, Paul; Heathcote, Michelle L.; Hobbs, Heather; Holmes, Duncan S.; Ioannou, Christos V.; Ramírez-Molina, César; Morse, Mary A.; Osborn, Ruth R.; Payne, J. J.; Pritchard, John B.; Rumsey, William L.; Tape, Daniel T.; Vicentini, G.; Whitworth, Caroline; Williamson, Rick

doi:10.1016/j.bmcl.2012.06.065

Cited by 23 publications

(16 citation statements)

References 13 publications

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“…This methionine conflict could explain the selectivity of compound 3 for JNK3 over JNK1. [27], 4QTD [28], 3ELJ [29], 4AWI [30], and 4L7F [31]) by pulling out the top six structures according to their resolution. The ligand is compound 3 docked into JNK3 (PDB 4WHZ [22]).…”

Section: Superimposition Of Jnk1 Jnk2 and Jnk3 Crystal Structuresmentioning

confidence: 99%

“…By combining these observations, we concluded that compound 4 induces the gatekeeper residue Met108 of JNK2 to move sufficiently to form a hydrophobic pocket similar to that of JNK3. [27], 4QTD [28], 3ELJ [29], 4AWI [30], and 4L7F [31]) by pulling out the top six structures according to their resolution. The ligand is compound 3 docked into JNK3 (PDB 4WHZ [22]).…”

Section: Superimposition Of Jnk1 Jnk2 and Jnk3 Crystal Structuresmentioning

confidence: 99%

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A Perspective on the Development of c-Jun N-terminal Kinase Inhibitors as Therapeutics for Alzheimer’s Disease: Investigating Structure through Docking Studies

Cho

Hah

2021

Biomedicines

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c-Jun N-terminal kinase (JNK) plays an important role in cell death caused by various stimuli. Because the isoform JNK3 is mainly expressed in the brain, it is believed to play a pivotal role in various neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), which still lack plausible therapeutics. To develop a novel and selective JNK3 inhibitor, we conducted a decadal review (2011 to 2021) of published articles on JNK inhibitors, particularly those focusing on a structural perspective and docking insights. We observed the structures of three isoforms of JNK, namely holo-proteins and co-crystal structures, with JNK3 inhibitors and summarized the significant structural aspects of selective JNK3 inhibitors as AD therapeutics.

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Section: Superimposition Of Jnk1 Jnk2 and Jnk3 Crystal Structuresmentioning

confidence: 99%

Section: Superimposition Of Jnk1 Jnk2 and Jnk3 Crystal Structuresmentioning

confidence: 99%

A Perspective on the Development of c-Jun N-terminal Kinase Inhibitors as Therapeutics for Alzheimer’s Disease: Investigating Structure through Docking Studies

Cho

Hah

2021

Biomedicines

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“…in Ref. ). The pIC 50 for the azaindoles binding to full length ASK1 vary from pIC 50 = 6.6 for Compound 4 to pIC 50 = 8.1 for Compound 3.…”

Section: Resultsmentioning

confidence: 98%

Crystal structures of ASK1‐inhibtor complexes provide a platform for structure‐based drug design

et al. 2013

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ASK1, a member of the MAPK Kinase Kinase family of proteins has been shown to play a key role in cancer, neurodegeneration and cardiovascular diseases and is emerging as a possible drug target. Here we describe a 'replacement-soaking' method that has enabled the highthroughput X-ray structure determination of ASK1/ligand complexes. Comparison of the X-ray structures of five ASK1/ligand complexes from 3 different chemotypes illustrates that the ASK1 ATP binding site is able to accommodate a range of chemical diversity and different binding modes. The replacement-soaking system is also able to tolerate some protein flexibility. This crystal system provides a robust platform for ASK1/ligand structure determination and future structure based drug design.

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“…Overlay with Human Jnk1alpha kinase with 4-phenyl-7-azaindole IKK2 inhibitor bound (PDB 4AWI) facilitated identification of the proposed binding pocket. 31 Based on this model, we propose that the 7-aza-indole scaffold interacts with the hinge region in the flipped conformation, that is, H-bonding to the peptide backbone of the hinge region ( Figure 3 ). The benzoic acid on ring B appears to occupy the ribose pocket and interacts with Lys-394.…”

Section: Resultsmentioning

confidence: 99%

Development of Potent PfCLK3 Inhibitors Based on TCMDC-135051 as a New Class of Antimalarials

et al. 2020

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The protein kinase Pf CLK3 plays a critical role in the regulation of malarial parasite RNA splicing and is essential for the survival of blood stage Plasmodium falciparum . We recently validated Pf CLK3 as a drug target in malaria that offers prophylactic, transmission blocking, and curative potential. Herein, we describe the synthesis of our initial hit TCMDC-135051 (1) and efforts to establish a structure–activity relationship with a 7-azaindole-based series. A total of 14 analogues were assessed in a time-resolved fluorescence energy transfer assay against the full-length recombinant protein kinase Pf CLK3, and 11 analogues were further assessed in asexual 3D7 (chloroquine-sensitive) strains of P. falciparum parasites. SAR relating to rings A and B was established. These data together with analysis of activity against parasites collected from patients in the field suggest that TCMDC-135051 (1) is a promising lead compound for the development of new antimalarials with a novel mechanism of action targeting Pf CLK3.

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4-Phenyl-7-azaindoles as potent, selective and bioavailable IKK2 inhibitors demonstrating good in vivo efficacy

Cited by 23 publications

References 13 publications

A Perspective on the Development of c-Jun N-terminal Kinase Inhibitors as Therapeutics for Alzheimer’s Disease: Investigating Structure through Docking Studies

A Perspective on the Development of c-Jun N-terminal Kinase Inhibitors as Therapeutics for Alzheimer’s Disease: Investigating Structure through Docking Studies

Crystal structures of ASK1‐inhibtor complexes provide a platform for structure‐based drug design

Development of Potent PfCLK3 Inhibitors Based on TCMDC-135051 as a New Class of Antimalarials

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