Structure-based design and synthesis of 1H-pyrazolo[3,4-d]pyrimidin-4-amino derivatives as Janus kinase 3 inhibitors

Yin, Yuan; Chen, Chengjuan; Yu, Ru-Nan; Wang, Zhijian; Zhang, Tiantai; Zhang, Dayong

doi:10.1016/j.bmc.2018.04.005

Cited by 17 publications

(4 citation statements)

References 21 publications

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“…Previous studies on developing covalently bound JAK3 inhibitors have revealed that residues Lys855, Leu905, Pro906, Cys909, Asp912, and Arg953 are involved in ligand binding [ 19 , 20 , 21 , 22 , 23 , 26 , 28 ]. From the key residues in the multiple sequence alignment ( Figure S1 , Table 1 ), one can conclude that the most unique residue for selective JAK3 binding is cysteine 909.…”

Section: Resultsmentioning

confidence: 99%

“…Due to the highly conserved structural features of the ATP binding pocket, it has been challenging to achieve high selectivity among the JAK family. Many recent developments of JAK3 inhibitors have been focused on a JAK3 unique cysteine residue (CYS909) by forming a covalent bond with JAK3 inhibitors [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. The idea of developing an inhibitor that can covalently bind to cysteine 909 was from other covalent drugs such as afatinib, osimertinib, and ibrutinib ( Figure 2 ).…”

Section: Introductionmentioning

confidence: 99%

“…Three drugs in Figure 2 shared a common α,β-unsaturated amide moiety to allow the Michael addition to the target protein via covalent binding. A number of JAK3 covalently bound inhibitors have been reported and some have been studied under various stages of clinical trials [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

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Docking and Selectivity Studies of Covalently Bound Janus Kinase 3 Inhibitors

Zhong

Almahmoud

2023

IJMS

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The Janus kinases (JAKs) are a family of non-receptor cytosolic protein kinases critical for immune signaling. Many covalently bound ligands of JAK3 inhibitors have been reported. To help design selective JAK inhibitors, in this paper, we used five model proteins to study the subtype selectivity of and the mutational effects on inhibitor binding. We also compared the Covalent Dock programs from the Schrodinger software suite and the MOE software suite to determine which method to use for the drug design of covalent inhibitors. Our results showed that the docking affinity from 4Z16 (JAK3 wild-type model), 4E4N (JAK1), 4D1S (JAK2), and 7UYT (TYK2) from the Schrödinger software suite agreed well with the experimentally derived binding free energies with small predicted mean errors. However, the data from the mutant 5TTV model using the Schrödinger software suite yielded relatively large mean errors, whereas the MOE Covalent Dock program gave small mean errors in both the wild-type and mutant models for our model proteins. The docking data revealed that Leu905 of JAK3 and the hydrophobic residue at the same position in different subtypes (Leu959 of JAK1, Leu932 of JAK2, and Val981 of TYK2) is important for ligand binding to the JAK proteins. Arg911 and Asp912 of JAK3, Asp939 of JAK2, and Asp988 of TYK2 can be used for selective binding over JAK1, which contains Lys965 and Glu966 at the respective positions. Asp1021, Asp1039, and Asp1042 can be utilized for JAK1-selective ligand design, whereas Arg901 and Val981 may help guide TYK2-selective molecule design.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Docking and Selectivity Studies of Covalently Bound Janus Kinase 3 Inhibitors

Zhong

Almahmoud

2023

IJMS

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“…A recent series of three works concerning the design and development of JAK3 selective inhibitors resulted from the joined efforts of two Chinese teams. The articles explore the design and synthesis of 1H-pyrazolo[3,4-d]pyrimidin-4-amino derivatives [ 138 ], pyrimidine-4,6-diamine derivatives [ 139 ] and 4- or 6-phenyl- pyrimidine derivatives [ 140 ], respectively. The three studies share a common pattern consisting in the design of derivatives, in vitro evaluation and a docking analysis to better understand the interaction framework and explain the selectivity.…”

Section: Enhancing Jakis Discovery Through Structure-based Drug Dementioning

confidence: 99%

Inside Perspective of the Synthetic and Computational Toolbox of JAK Inhibitors: Recent Updates

et al. 2020

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The mechanisms of inflammation and cancer are intertwined by complex networks of signaling pathways. Dysregulations in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway underlie several pathogenic conditions related to chronic inflammatory states, autoimmune diseases and cancer. Historically, the potential application of JAK inhibition has been thoroughly explored, thus triggering an escalation of favorable results in this field. So far, five JAK inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of different diseases. Considering the complexity of JAK-depending processes and their involvement in multiple disorders, JAK inhibitors are the perfect candidates for drug repurposing and for the assessment of multitarget strategies. Herein we reviewed the recent progress concerning JAK inhibition, including the innovations provided by the release of JAKs crystal structures and the improvement of synthetic strategies aimed to simplify of the industrial scale-up.

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Insight into Janus kinases specificity: From molecular architecture to cancer therapeutics

Wei,

Lu,

Yao

et al. 2024

MedComm – Oncology

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Janus Kinases (JAKs) play a crucial role as therapeutic targets for various cancers. However, the current JAK inhibitors (JAKi) available have limited therapeutic benefits due to their lack of selectivity. This review focuses on the structural analysis to elucidate the molecular determinants of JAKs specificity and the discovery and design of selective JAKi. It includes descriptions and comparison of different JAK structures and their binding sites, a comparative analysis of JAKi and their binding modes, detailed interaction fingerprints (IFPs), and an extensive structure‐selectivity relationship (SSRs). Moreover, the review also explores the challenges and possibilities of using computational structure‐based methods for discovering and designing selective JAKi. Other structure‐based approaches, such as targeting the pseudokinase domain, as well as covalent and allosteric designs, are also covered. Based on this analysis, key determinants corresponding to JAK specificity and rational medicinal chemistry strategies are proposed to facilitate the development of highly selective JAKi. Overall, we aim to enhance the understanding of JAK specificity and explore strategies that can lead to the discovery of effective and selective JAKi in cancer therapy, thus improving the prognosis for cancer patients.

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Structure-based design and synthesis of 1H-pyrazolo[3,4-d]pyrimidin-4-amino derivatives as Janus kinase 3 inhibitors

Cited by 17 publications

References 21 publications

Docking and Selectivity Studies of Covalently Bound Janus Kinase 3 Inhibitors

Docking and Selectivity Studies of Covalently Bound Janus Kinase 3 Inhibitors

Inside Perspective of the Synthetic and Computational Toolbox of JAK Inhibitors: Recent Updates

Insight into Janus kinases specificity: From molecular architecture to cancer therapeutics

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