Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors

Brasca, Maria Gabriella; Nesi, Marcella; Avanzi, Nilla; Ballinari, Dario; Bandiera, Tiziano; Bertrand, J. A.; Bindi, Simona; Canevari, Giulia; Carenzi, Davide; Casero, Daniele; Ceriani, Lucio; Ciomei, Marina; Cirla, Alessandra; Colombo, Maristella; Cribioli, Sabrina; Cristiani, Cinzia; Vedova, Franco Della; Fachin, Gabriele; Fasolini, Marina; Felder, E.; Galvani, Arturo; Isacchi, Antonella; Mirizzi, Danilo; Motto, Ilaria; Panzeri, A.; Pesenti, Enrico; Vianello, Paola; Gnocchi, Paola; Donati, Daniele

doi:10.1016/j.bmc.2014.06.025

Cited by 20 publications

(10 citation statements)

References 39 publications

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“…42 The Supporting Information in Figure S2 showed that both models were mostly found in the favored region with a value of 92.6% for JAK1 and 92.1% for JAK3. Since there is no co-crystal structure of the JAK2-tofacitinib complex, the pyrrole-3carboxamide in JAK2 (PDB code: 4D0X 21 ) was replaced by tofacitinib via superimposition with the tofacitinib/JAK1(3) complex using the UCSF Chimera package. 43 The protonation states of all ionizable amino acids were characterized using PROPKA 3.0.…”

Section: Methodsmentioning

confidence: 99%

“…The complexation between tofacitinib and JAKs (JAK1, JAK2, and JAK3) has been studied experimentally and theoretically. The three-dimensional (3D) structures of JAK1 and JAK3 in complex with tofacitinib were crystallized, , while the X-ray structure of JAK2 was co-crystalized with pyrrole-3-carboxamide . They have sequence identity from CLUSTALW in a range of 46–55% and sequence similarity of 61–71% (see Figure S1 in the Supporting Information).…”

Section: Introductionmentioning

confidence: 99%

“…The three-dimensional (3D) structures of JAK1 and JAK3 in complex with tofacitinib were crystallized, 19,20 while the X-ray structure of JAK2 was co-crystalized with pyrrole-3-carboxamide. 21 They have sequence identity from CLUSTALW 22 in a range of 46−55% and sequence similarity of 61−71% (see Figure S1 in the Supporting Information). By superimposition on the three complexes (Figure 1A), the active conformation of JAKs, in which the activation loop (A loop) is closed into the active site, is found in the ligand-bound form.…”

Section: Introductionmentioning

confidence: 99%

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Insights into the Binding Recognition and Susceptibility of Tofacitinib toward Janus Kinases

et al. 2020

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Janus kinases (JAKs) are enzymes involved in signaling pathways that affect hematopoiesis and immune cell functions. JAK1, JAK2, and JAK3 play different roles in numerous diseases of the immune system and have also been considered as potential targets for cancer therapy. In the present study, the susceptibility of the oral JAK inhibitor tofacitinib against these three JAKs was elucidated using the 500-ns molecular dynamics (MD) simulations and free energy calculations based on MM-PB(GB)SA, QM/MM-GBSA (PM3 and SCC-DFTB), and SIE methods. The obtained results revealed that tofacitinib could interact with all JAKs at the ATP-binding site via electrostatic attraction, hydrogen bond formation, and in particular van der Waals interaction. The conserved glutamate and leucine residues (E957 and L959 of JAK1, E930 and L932 of JAK2, and E903 and L905 of JAK3) located in the hinge region stabilized tofacitinib binding through strongly formed hydrogen bonds. Complexation with the incoming tofacitinib led to a closed conformation of the ATP-binding site and a decreased protein fluctuation at the glycine loop of the JAK protein. The binding affinities of tofacitinib/JAKs were ranked in the order of JAK3 > JAK2 ∼ JAK1, which are in line with the reported experimental data.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Insights into the Binding Recognition and Susceptibility of Tofacitinib toward Janus Kinases

et al. 2020

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“…167 This method worked but the yield was low. The best yield for this reaction was obtained by using a patent method 168 where they used Fe and NH4Cl as shown in Scheme 3.4.…”

Section: Synthesis Of Control Phenylacetylene Armsmentioning

confidence: 99%

Supramolecular BODIPY Dye Architectures for Advanced Light Harvesting and Energy Transfer Applications

Yousaf¹

2022

Preprint

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Shape-persistent phenylacetylene macrocycles have been explored in a number of optoelectronic and light-harvesting applications, including two-photon absorption. Likewise, BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes) dyes have also been extensively used in material applications, owing to their tunable, intense absorption and sharp emission spectra exhibiting high quantum yields. Combining these two architectures, this thesis presents a derivative where a BODIPY is contained orthogonally within the phenylacetylene-macrocycle. This structure was inspired by photosystem II antennae complexes where energy is obsorbed by antennae complexes and funneled down to a reaction centre. Specifically, this family of molecules uses the phenylacetylene macrocycle to harvest the light and transfer it to the BODIPY core, and this has been observed by examining the fluorescence emission from the BODIPY (Figure 1). This novel dye design if coupled to a donor (D) and acceptor (A) capable of anchoring to TiO2 could be modified to become a π-spacer (i.e. D-π-A motif) for dye-sensitized solar cells resulting in panchromatic absorption, and ultimately more efficient devices.

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“…Interestingly, this pair of targets provided 31 similarity records from 27 Hsp90 ligands and 17 JAK2 compounds, belonging to different chemotypes and known binding mode (see Supplementary Table S3 in the Supporting Material). Among the identified pairs of Hsp90- and JAK2-ligands, an example of particular interest comes from the comparison of the crystallographic compounds with HET IDs 73S (in complex with Hsp90, PDB code 5LRL, DOI: 10.2210/pdb5LRL/pdb) and VVQ (crystallized with JAK2, PDB code: 4D0W) ( 44 ), which provided similarity scores of 0.884 (MACCS) and 0.238 (ECFP4). Supplementary Figure S1 highlights the 2D structure of the selected pair of ligands, and the experimentally observed binding mode in their respective targets.…”

Section: Case Studiesmentioning

confidence: 99%

LigAdvisor: a versatile and user-friendly web-platform for drug design

Pinzi

Tinivella

Gagliardelli

et al. 2021

Nucleic Acids Research

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Although several tools facilitating in silico drug design are available, their results are usually difficult to integrate with publicly available information or require further processing to be fully exploited. The rational design of multi-target ligands (polypharmacology) and the repositioning of known drugs towards unmet therapeutic needs (drug repurposing) have raised increasing attention in drug discovery, although they usually require careful planning of tailored drug design strategies. Computational tools and data-driven approaches can help to reveal novel valuable opportunities in these contexts, as they enable to efficiently mine publicly available chemical, biological, clinical, and disease-related data. Based on these premises, we developed LigAdvisor, a data-driven webserver which integrates information reported in DrugBank, Protein Data Bank, UniProt, Clinical Trials and Therapeutic Target Database into an intuitive platform, to facilitate drug discovery tasks as drug repurposing, polypharmacology, target fishing and profiling. As designed, LigAdvisor enables easy integration of similarity estimation results with clinical data, thereby allowing a more efficient exploitation of information in different drug discovery contexts. Users can also develop customizable drug design tasks on their own molecules, by means of ligand- and target-based search modes, and download their results. LigAdvisor is publicly available at https://ligadvisor.unimore.it/.

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Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors

Cited by 20 publications

References 39 publications

Insights into the Binding Recognition and Susceptibility of Tofacitinib toward Janus Kinases

Insights into the Binding Recognition and Susceptibility of Tofacitinib toward Janus Kinases

Supramolecular BODIPY Dye Architectures for Advanced Light Harvesting and Energy Transfer Applications

LigAdvisor: a versatile and user-friendly web-platform for drug design

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