Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5-<i>d</i>]pyrrolo[2,3-<i>b</i>]pyridine Inhibitors

Hart, Amy C.; Schroeder, G.; Wan, Honghe; Grebinski, James; Inghrim, Jennifer; Kempson, James; Guo, Junqing; Pitts, William J.; Tokarski, John S.; Sack, John S.; Khan, Javed; Lippy, Jonathan; Lorenzi, Matthew V.; You, Dan; McDevitt, Theresa M.; Vuppugalla, Ragini; Zhang, Yueping; Lombardo, Louis J.; Trainor, George L.; Purandare, Ashok V.

doi:10.1021/acsmedchemlett.5b00225

Cited by 12 publications

(9 citation statements)

References 13 publications

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“…In addition, NPQ-C6 fit better into the JAK2 ATP-binding site. This compound showed a good steric and electronic complementarity with the binding site, being observed the existence of two hydrogen bonds, one of them between the residue Leu 932 and the carbonyl group of the NPQ nucleus, as well as another hydrogen bond between Ser 936 and the carbonyl group of the coumarin moiety which are similar to those observed for known JAK2 inhibitors (Zak et al, 2013; Hart et al, 2015).…”

Section: Discussionsupporting

confidence: 58%

A Novel Naphthoquinone-Coumarin Hybrid That Inhibits BCR-ABL1-STAT5 Oncogenic Pathway and Reduces Survival in Imatinib-Resistant Chronic Myelogenous Leukemia Cells

et al. 2019

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BCR-ABL1-STAT5 is an oncogenic signaling pathway in human chronic myelogenous leukemia (CML) and it represents a valid target for anti-CML drug design. Resistance to direct BCR-ABL1 inhibitors is a common clinical issue, so STAT5 inhibition has become an interesting alternative target. In this study, the effects of NPQ-C6, a novel naphtoquinone-coumarin conjugate, were evaluated on human CML-derived K562 cells. Live-Cell Imaging analysis revealed that NPQ-C6 inhibited 2D (IC50AUC = 1.4 ± 0.6 μM) growth of CML cells. NPQ-C6 increased sub-G1 and reduced G0/G1 cell cycle phases in a dose- and time-dependent manner. This effect on cell cycle was related to increased levels of apoptotic nuclei, cleavage of caspase-3, -9, and PARP and annexin V-positive cells. NPQ-C6 increased γH2AX, a double-strand DNA break marker. NPQ-C6 showed a wide range of modulatory effects on cell signaling through an early increased phosphorylation of JNK, P38-MAPK and AKT, and decreased phosphorylation of ERK1/2, BCR-ABL1, and STAT5. NPQ-C6 inhibited expression of c-MYC and PYM-1, two target gene products of BCR-ABL1/STAT5 signaling pathway. Cytokine-induced activation of STAT5/STAT3-dependent transcriptional and DNA binding activities were also inhibited by NPQ-C6. Notably, NPQ-C6 maintained its activity on BCR-ABL1/STAT5/c-MYC/PIM-1 oncogenic pathway in imatinib-resistant cells. Molecular modeling suggested BCR-ABL1 and JAK2 proteins as NPQ-C6 targets. In summary, our data show a novel multikinase modulator that might be therapeutically effective in BCR-ABL1-STAT5-related malignancies.

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Section: Discussionsupporting

confidence: 58%

A Novel Naphthoquinone-Coumarin Hybrid That Inhibits BCR-ABL1-STAT5 Oncogenic Pathway and Reduces Survival in Imatinib-Resistant Chronic Myelogenous Leukemia Cells

et al. 2019

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“…A cross-docking exercise was then carried out to validate the ability of the docking protocol to reproduce the available experimental complexes and to find out the structures endowed with the better propensity to reproduce not only the native binding mode but also the one displayed by other structures ( Figure S1 ). As a result of the cross-docking, we selected the PDB-IDs 4IVD, 20 5CF6, 21 and 6GLA( 22 ) as representatives of JAK1, JAK2, and JAK3 subtypes. In Figure 7 , we report the main interactions established by the native compounds cocrystallized with the structures chosen to represent the three JAK subtypes.…”

Section: Resultsmentioning

confidence: 99%

“…Representation of the binding sites of the JAK1, JAK2, and JAK3 structures in complex with the native ligands that were selected for the docking calculations (PDB-ID: 4IVD, 5CF6, and 6GLA, respectively). − The conserved residues are represented as sticks with carbon atoms colored in white, while specific amino acids are differently colored (orange, yellow, and green for JAK1, JAK2, and JAK3, respectively). Hydrogen bonds are explicitly reported as black dots.…”

Section: Resultsmentioning

confidence: 99%

“…The crystal structures of JAK1, JAK2, and JAK3 were retrieved from Protein Data Bank (PDB-IDs: 4IVd, 5CF6, and 6GLA). − The definition of the binding site pocket for the different JAK subtypes was provided by the coordinates of the cocrystallized ligands. Once the ligand and protein were prepared, the grid was generated according to the largest ligand and used as the reference to perform the cross-docking analysis (box size of 20 Å per side).…”

Section: Experimental: In Silico Modelingmentioning

confidence: 99%

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Targeting the JAK/STAT Pathway: A Combined Ligand- and Target-Based Approach

Gálvez-Llompart

Ocello

Rullo

et al. 2021

J. Chem. Inf. Model.

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Janus kinases (JAKs) are a family of proinflammatory enzymes able to mediate the immune responses and the inflammatory cascade by modulating multiple cytokine expressions as well as various growth factors. In the present study, the inhibition of the JAK–signal transducer and activator of transcription (STAT) signaling pathway is explored as a potential strategy for treating autoimmune and inflammatory disorders. A computationally driven approach aimed at identifying novel JAK inhibitors based on molecular topology, docking, and molecular dynamics simulations was carried out. For the best candidates selected, the inhibitory activity against JAK2 was evaluated in vitro . Two hit compounds with a novel chemical scaffold, 4 (IC 50 = 0.81 μM) and 7 (IC 50 = 0.64 μM), showed promising results when compared with the reference drug Tofacitinib (IC 50 = 0.031 μM).

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“…Further ADME profiling indicated that 1 was rapidly metabolized across species and was susceptible to generation of reactive metabolites (vide inf ra), which prevented its further progression. Herein we report ADMET and structure-guided optimization of heterocycles at the C-4 position of the imidazopyrrolopyridine core leading to the discovery of a highly selective JAK2 inhibitor, BMS-911543 (11), as a clinical candidate for the treatment of MPNs. Earlier we have reported biological characterization of BMS-911543.…”

mentioning

confidence: 99%

Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms

Wan

Schroeder

Hart

et al. 2015

ACS Med. Chem. Lett.

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JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.

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Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5-d]pyrrolo[2,3-b]pyridine Inhibitors

Cited by 12 publications

References 13 publications

A Novel Naphthoquinone-Coumarin Hybrid That Inhibits BCR-ABL1-STAT5 Oncogenic Pathway and Reduces Survival in Imatinib-Resistant Chronic Myelogenous Leukemia Cells

A Novel Naphthoquinone-Coumarin Hybrid That Inhibits BCR-ABL1-STAT5 Oncogenic Pathway and Reduces Survival in Imatinib-Resistant Chronic Myelogenous Leukemia Cells

Targeting the JAK/STAT Pathway: A Combined Ligand- and Target-Based Approach

Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms

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