The Discovery of 3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, a Highly Ligand Efficient and Efficacious Janus Kinase 1 Selective Inhibitor with Favorable Pharmacokinetic Properties

Siu, Tony; Brubaker, Jason D.; Fuller, Peter H.; Torres, Luis Ángel Pérula de; Zeng, Hongbo; Close, Joshua; Mampreian, Dawn M.; Shi, Feng; Liu, Duan; Fradera, Xavier; Johnson, Kevin C.; Bays, Nathan; Elma, Kadić; Fang, He; Goldenblatt, Peter; Shaffer, Lynsey; Patel, Sangita; Lesburg, Charles A.; Alpert, Carla; Dorosh, Lauren; Deshmukh, Sujal V.; Yu, Hongshi; Klappenbach, Joel A.; Elwood, Fiona; Dinsmore, Christopher J.; Fernández, Rafael; Moy, Lily Y.; Young, Jonathan R.

doi:10.1021/acs.jmedchem.7b01135

Cited by 15 publications

(8 citation statements)

References 46 publications

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“…The IC 50 values and molecular structures are shown in Table S1. Moreover, we downloaded three sets of inactive molecules from ZINC, which contained 2000, 10,000, and 20,000 molecules. − …”

Section: Methodsmentioning

confidence: 99%

Machine Learning Models Based on Molecular Fingerprints and an Extreme Gradient Boosting Method Lead to the Discovery of JAK2 Inhibitors

Yang

Tao²,

Chen

et al. 2019

J. Chem. Inf. Model.

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Developing Janus kinase 2 (JAK2) inhibitors has become a significant focus for small-molecule drug discovery programs in recent years because the inhibition of JAK2 may be an effective approach for the treatment of myeloproliferative neoplasm. Here, based on three different types of fingerprints and Extreme Gradient Boosting (XGBoost) methods, we developed three groups of models in that each group contained a classification model and a regression model to accurately acquire highly potent JAK2 kinase inhibitors from the ZINC database. The three classification models resulted in Matthews correlation coefficients of 0.97, 0.94, and 0.97. Docking methods including Glide and AutoDock Vina were employed to evaluate the virtual screening effectiveness of our classification models. The R 2 of three regression models were 0.80, 0.78, and 0.80. Finally, 13 compounds were biologically evaluated, and the results showed that the IC50 values of six compounds were identified to be less than 100 nM. Among them, compound 9 showed high activity and selectivity in that its IC50 value was less than 1 nM against JAK2 while 694 nM against JAK3. The strategy developed may be generally applicable in ligand-based virtual screening campaigns.

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Section: Methodsmentioning

confidence: 99%

Machine Learning Models Based on Molecular Fingerprints and an Extreme Gradient Boosting Method Lead to the Discovery of JAK2 Inhibitors

Yang

Tao²,

Chen

et al. 2019

J. Chem. Inf. Model.

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“…Molecular docking of ZT55 into the three-dimensional X-ray structures of JAK family members (JAK1, PDB code: 5WO4; JAK2, PDB code: 5UT6; JAK3, PDB code: 5TTU) was simulated using the graphical user interface DS-CDOCKER with Discovery Studio [13–15]. The protein active sites for docking were determined from the inhibitor binding sites in co-crystal structures of the protein complexes retrieved from the RCSB Protein Data Bank.…”

Section: Methodsmentioning

confidence: 99%

Discovery and evaluation of ZT55, a novel highly-selective tyrosine kinase inhibitor of JAK2V617F against myeloproliferative neoplasms

Chen

Yang

et al. 2019

J Exp Clin Cancer Res

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BackgroundThe JAK2-STAT signaling pathway plays a critical role in myeloproliferative neoplasms (MPN). An activating mutation in JAK2 (V617F) is present in ~ 95% of polycythemia vera, essential thrombocythemia, and primary myelofibrosis cases. This study aims to explore the selective JAK2V617F inhibitor, evaluate the efficacy and possible mechanism of ZT55 on MPN.MethodsHTRF assays were conducted to evaluate the selective inhibition of ZT55 for JAKs. Cell apoptosis, proliferation, and cycle arrest assays were performed to examine the effect of ZT55 on HEL cell line with JAK2V617F mutation in vitro. Western analysis was used to monitor the expression and activity of proteins on JAK2/STAT pathway. A mice xenograft model was established to evaluate the antitumor efficacy of ZT55 in vivo. Peripheral blood samples from patients with the JAK2V617F mutation were collected to estimate the effect of ZT55 on erythroid colony formation by colony-forming assay.ResultsWe found that ZT55 showed a selective inhibition of a 0.031 μM IC50 value against JAK2. It exhibited potent effects on the cellular JAK-STAT pathway, inhibiting tyrosine phosphorylation in JAK2V617F and downstream STAT3/5 transcription factors. ZT55 inhibited the proliferation of the JAK2V617F-expressing HEL cell line, leading to cell cycle arrest at the G2/M phase and induction of caspase-dependent apoptosis. Notably, ZT55 also significantly suppressed the growth of HEL xenograft tumors in vivo. Further evaluation indicated that ZT55 blocked erythroid colony formation of peripheral blood hematopoietic progenitors from patients carrying the JAK2V617F mutation.ConclusionThese results suggest that ZT55 is a highly-selective JAK2 inhibitor that can induce apoptosis of human erythroleukemia cells by inhibiting the JAK2-STAT signaling.Electronic supplementary materialThe online version of this article (10.1186/s13046-019-1062-x) contains supplementary material, which is available to authorized users.

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“…These results correspond to the IC 50 values of pyrazolone derivatives consisting of chloro-methoxyphenyl-amino groups (19 nM) and pyrrole carboxamide (20 nM) toward JAK2 from previous reports. 48,49 The IC 50 values of the three mentioned compounds toward JAK3 were 18.90 ± 1.13 nM for 3h, 18.42 ± 0.34 nM for TK4b, and 15.80 ± 0.81 nM for TK4g. Previous reports showed that an aminopyrazole analogue with three chlorine atoms, which is to some extent similar to compound 3h compound, gave IC 50 values toward JAK2 and JAK3 of 2.2 and 3.5 nM, respectively.…”

Section: Virtual Screeningmentioning

confidence: 97%

Pharmacophore-Based Virtual Screening and Experimental Validation of Pyrazolone-Derived Inhibitors toward Janus Kinases

et al. 2022

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Janus kinases (JAKs) are nonreceptor protein tyrosine kinases that play a role in a broad range of cell signaling. JAK2 and JAK3 have been involved in the pathogenesis of common lymphoid-derived diseases and leukemia cancer. Thus, inhibition of both JAK2 and JAK3 can be a potent strategy to reduce the risk of these diseases. In the present study, the pharmacophore models built based on the commercial drug tofacitinib and the JAK2/3 proteins derived from molecular dynamics (MD) trajectories were employed to search for a dual potent JAK2/3 inhibitor by a pharmacophore-based virtual screening of 54 synthesized pyrazolone derivatives from an in-house data set. Twelve selected compounds from the virtual screening procedure were then tested for their inhibitory potency against both JAKs in the kinase assay. The in vitro kinase inhibition experiment indicated that compounds 3h, TK4g, and TK4b can inhibit both JAKs in the low nanomolar range. Among them, the compound TK4g showed the highest protein kinase inhibition with the half-maximal inhibitory concentration (IC 50 ) value of 12.61 nM for JAK2 and 15.80 nM for JAK3. From the MD simulations study, it could be found that the sulfonamide group of TK4g can form hydrogen bonds in the hinge region at residues E930 and L932 of JAK2 and E903 and L905 of JAK3, while van der Waals interaction also plays a dominant role in ligand binding. Altogether, TK4g, found by virtual screening and biological tests, could serve as a novel therapeutical lead candidate.

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The Discovery of 3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, a Highly Ligand Efficient and Efficacious Janus Kinase 1 Selective Inhibitor with Favorable Pharmacokinetic Properties

Cited by 15 publications

References 46 publications

Machine Learning Models Based on Molecular Fingerprints and an Extreme Gradient Boosting Method Lead to the Discovery of JAK2 Inhibitors

Machine Learning Models Based on Molecular Fingerprints and an Extreme Gradient Boosting Method Lead to the Discovery of JAK2 Inhibitors

Discovery and evaluation of ZT55, a novel highly-selective tyrosine kinase inhibitor of JAK2V617F against myeloproliferative neoplasms

Pharmacophore-Based Virtual Screening and Experimental Validation of Pyrazolone-Derived Inhibitors toward Janus Kinases

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