Dual Inhibition of TYK2 and JAK1 for the Treatment of Autoimmune Diseases: Discovery of ((S)-2,2-Difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841)

Fensome, Andrew; Ambler, Catherine M.; Arnold, Eric P.; Banker, Mary Ellen; Brown, Matthew F.; Chrencik, Jill E.; Clark, James D.; Dowty, Martin E.; Efremov, Ivan; Flick, Andrew C.; Gerstenberger, Brian S.; Gopalsamy, Ariamala; Hayward, Matthew M.; Hegen, Martin; Hollingshead, Brett D.; Jussif, Jason; Knafels, John D.; Limburg, David C.; Lin, David W.; Lin, Tsung H.; Pierce, Betsy S.; Saiah, Eddine; Sharma, Raman; Symanowicz, Peter T.; Telliez, Jean‐Baptiste; Trujillo, John I.; Vajdos, F.F.; Vincent, Fabien; Wan, Zhengming; Li, Xing; Yang, Xiaojing; Yang, Xin; Zhang, Liying

doi:10.1021/acs.jmedchem.8b00917

Cited by 122 publications

(95 citation statements)

References 40 publications

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“…To avoid JAK2 inhibition mediated side effects, dual JAK1/TYK2 inhibition without influence on JAK2 signaling could be interesting. PF-06700841 is a new selective JAK inhibitor also mainly targeting TYK2 but also JAK1 76,77 .…”

Section: New Jak Related Molecules In Deveopment In CDmentioning

confidence: 99%

Efficacy of JAK inhibitors in Crohn’s Disease

Rogler

2019

Journal of Crohn's and Colitis

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Inhibition of Janus kinases in Crohn’s disease (CD) patients has shown conflicting results in clinical trials. Tofacitinib, a pan-JAK inhibitor showed efficacy in ulcerative colitis (UC) and has been approved for the treatment of patients with moderate to severe UC. In contrast, studies in patients suffering from CD were disappointing and the primary endpoint of clinical remission could not be met in the respective phase II induction and maintenance trials. Subsequently, the clinical development of tofacitinib was discontinued in CD. In contrast, efficacy of filgotinib, a selective JAK1 inhibitor, in CD patients was demonstrated in the randomized, double-blinded, placebo-controlled phase II FITZROY study. Upadacitinib also showed promising results in a phase II trial in moderate to severe CD. Subsequently phase III programs in CD have been initiated for both substances, which are still ongoing. Several newer molecules of this class of orally administrated immunosuppressants are tested in clinical programs. The concern of side effects of systemic JAK inhibition is addressed by either exclusively intestinal action or higher selectivity (Tyk2 inhibitors). In general, JAK inhibitors constitute a new promising class of drugs for the treatment of CD.

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Section: New Jak Related Molecules In Deveopment In CDmentioning

confidence: 99%

Efficacy of JAK inhibitors in Crohn’s Disease

Rogler

2019

Journal of Crohn's and Colitis

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“…GST-tagged recombinant human kinase domains of JAK1, JAK2, and JAK3 were purchased from Invitrogen. His-tagged recombinant human TYK2, mouse TYK2, and human TYK2 I960V mutant kinase domains were expressed in insect cell/baculovirus systems and purified using a two-step affinity and size exclusion purification method 13 .…”

Section: Methodsmentioning

confidence: 99%

“…This technology is separation-based, allowing direct detection of fluorescently labeled substrates and products with separations controlled by a combination of vacuum pressure and electric field strength optimized for the peptide substrate. See the Supporting Information for commercial and sequence information 13,21 .…”

Section: Methodsmentioning

confidence: 99%

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Demonstration of In Vitro to In Vivo Translation of a TYK2 Inhibitor That Shows Cross Species Potency Differences

Gerstenberger

Banker

Clark

et al. 2020

Sci Rep

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Translation of modulation of drug target activity to therapeutic effect is a critical aspect for all drug discovery programs. In this work we describe the profiling of a non-receptor tyrosine-protein kinase (TYK2) inhibitor which shows a functionally relevant potency shift between human and preclinical species (e.g. murine, dog, macaque) in both biochemical and cellular assays. Comparison of the structure and sequence homology of TYK2 between human and preclinical species within the ATP binding site highlights a single amino acid (I960 → V) responsible for the potency shift. Through TYK2 kinase domain mutants and a TYK2 980I knock-in mouse model, we demonstrate that this single amino acid change drives a functionally relevant potency difference that exists between human and all evaluated preclinical species, for a series of TYK2 inhibitors which target the ATP binding site.

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“…To visualize the prediction results of our model, we selected three representative compound-protein pairs ranked around 10%, 50% and 90% in terms of the AUC scores, and plotted the corresponding true labels and the predicted interaction sites in the compound structures and protein sequences (Fig 3b-d). The example pair ranked around top 10% was a tyrosine kinase inhibitor binding to TYK2 (Fig 3b, PDB ID: 6DBK) [35]. The top 40% of the predicted interaction sites (atoms) in the compound covered all the true interaction sites, and the high prediction scores were also appeared around the true interaction sites along the protein sequence.…”

Section: Performance Evaluation On Pairwise Non-covalent Interaction mentioning

confidence: 99%

MONN: a Multi-Objective Neural Network for Predicting Pairwise Non-Covalent Interactions and Binding Affinities between Compounds and Proteins

Wan

Shu

et al. 2019

Preprint

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Computational approaches for inferring the mechanisms of compound-protein interactions (CPIs) can greatly facilitate drug development. Recently, although a number of deep learning based methods have been proposed to predict binding affinities and attempt to capture local interaction sites in compounds and proteins through neural attentions, they still lack a systematic evaluation on the interpretability of the identified local features. In addition, in these previous approaches, the exact matchings between interaction sites from compounds and proteins, which are generally important for understanding drug mechanisms of action, still remain unknown. Here, we compiled the first benchmark dataset containing the inter-molecular non-covalent interactions for more than 10,000 compound-protein pairs, and used it to systematically evaluate the interpretability of neural attentions in existing prediction models. We developed a multi-objective neural network, called MONN, to predict both non-covalent interactions and binding affinity for a given compound-protein pair. MONN uses convolution neural networks on molecular graphs of compounds and primary sequences of proteins to effectively capture the intrinsic features from both inputs, and also takes advantage of the predicted non-covalent interactions to further boost the accuracy of binding affinity prediction. Comprehensive evaluation demonstrated that while the previous neural attention based approaches fail to exhibit satisfactory interpretability results without extra supervision, MONN can successfully predict non-covalent interactions on our benchmark dataset as well as another independent dataset derived from the Protein Data Bank (PDB). Moreover, MONN can outperform other state-of-the-art methods in predicting compound-protein binding affinities. In addition, the pairwise interactions predicted by MONN displayed compatible and accordant patterns in chemical properties, which provided another evidence to support the strong predictive power of MONN. These results suggested that MONN can offer a powerful tool in predicting binding affinities of compound-protein pairs and also provide useful insights into understanding the molecular mechanisms of compound-protein interactions, which thus can greatly advance the drug discovery process. The source code of the MONN model and the dataset creation process can be downloaded from https://github.com/lishuya17/MONN.

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Dual Inhibition of TYK2 and JAK1 for the Treatment of Autoimmune Diseases: Discovery of ((S)-2,2-Difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841)

Cited by 122 publications

References 40 publications

Efficacy of JAK inhibitors in Crohn’s Disease

Efficacy of JAK inhibitors in Crohn’s Disease

Demonstration of In Vitro to In Vivo Translation of a TYK2 Inhibitor That Shows Cross Species Potency Differences

MONN: a Multi-Objective Neural Network for Predicting Pairwise Non-Covalent Interactions and Binding Affinities between Compounds and Proteins

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