Discovery and Development of Janus Kinase (JAK) Inhibitors for Inflammatory Diseases

Clark, James D.; Flanagan, Mark E.; Telliez, Jean‐Baptiste

doi:10.1021/jm401490p

Cited by 490 publications

(555 citation statements)

References 81 publications

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“…In addition to targeting multiple cytokines, a downstream approach to cytokine inhibition is characterized by its ability to achieve partial and reversible inhibition through appropriate dosing. In contrast to biological therapies, which effect near-complete inhibition of cytokine signaling during a dosing period, intracellular inhibition with a small molecule affords the ability to modulate JAK-dependent signaling downstream, allowing the potential for greater control of the inflammatory and immunomodulatory response throughout the dosing period (9). This partial and reversible inhibition of multiple cytokine pathways with a small molecule, compared with inhibition of a single cytokine pathway with a biological therapy, could offer a differentiated therapeutic profile.…”

Section: Jak Inhibition Of Multiple Inflammatory Pathwaysmentioning

confidence: 99%

JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines

Danese¹,

Grisham

Hodge

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Section: Jak Inhibition Of Multiple Inflammatory Pathwaysmentioning

confidence: 99%

JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines

Danese¹,

Grisham

Hodge

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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143

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“…JAK kinase inhibitors (JAKis) have been intensively and successfully pursued over the last two decades (2,3) and could be considered poster children of network pharmacology. JAK kinases (JAK1/2/3 and TYK2) are the initial mediators of signaling pathways triggered by many cytokines and hematopoietic growth factors, and activate transducers of the STAT family to prompt cell activation and phenotypic differentiation in all immunocyte lineages (4).…”

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confidence: 99%

“…The therapeutic potential of inhibiting cytokine signaling in autoimmune diseases led to the development of first-generation JAKi (2,3,5), with good kinome-wide specificity, but shared crossreactivity against several JAKs. Several proved to have clinical efficacy [e.g., against rheumatoid arthritis (RA), ulcerative colitis, psoriasis, or myeloproliferative diseases (6)].…”

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confidence: 99%

Network pharmacology of JAK inhibitors

Moodley

Yoshida

Mostafavi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Small-molecule inhibitors of the Janus kinase family (JAKis) are clinically efficacious in multiple autoimmune diseases, albeit with increased risk of certain infections. Their precise mechanism of action is unclear, with JAKs being signaling hubs for several cytokines. We assessed the in vivo impact of pan-and isoform-specific JAKi in mice by immunologic and genomic profiling. Effects were broad across the immunogenomic network, with overlap between inhibitors. Natural killer (NK) cell and macrophage homeostasis were most immediately perturbed, with network-level analysis revealing a rewiring of coregulated modules of NK cell transcripts. The repression of IFN signature genes after repeated JAKi treatment continued even after drug clearance, with persistent changes in chromatin accessibility and phospho-STAT responsiveness to IFN. Thus, clinical use and future development of JAKi might need to balance effects on immunological networks, rather than expect that JAKis affect a particular cytokine response and be cued to long-lasting epigenomic modifications rather than by short-term pharmacokinetics.JAK inhibitor | tofacitinib | systems pharmacology A drug's mechanism of action usually refers to the specific molecular or biologic activity that it perturbs, and drug optimization aims at maximizing potency and specificity vs. this target. However, the molecular target may be far removed from the processes that ultimately drive the therapeutic effect. For instance, even though the target is known, it remains unclear which cell or pathway is pivotally affected by anti-PD1 during cancer immunotherapy. Given the interdependencies of cellular and molecular players in biological systems, a drug is likely to have effects far broader than its molecular target. Conversely, it may be hampered by inherent resistance to perturbation of interconnected networks. This complexity is encapsulated in the concepts of network pharmacology, which proposes that drug development focus on network-level alterations, rather than on exquisite specificity for an individual target (1).JAK kinase inhibitors (JAKis) have been intensively and successfully pursued over the last two decades (2, 3) and could be considered poster children of network pharmacology. JAK kinases (JAK1/2/3 and TYK2) are the initial mediators of signaling pathways triggered by many cytokines and hematopoietic growth factors, and activate transducers of the STAT family to prompt cell activation and phenotypic differentiation in all immunocyte lineages (4). The cytokine network is an unusually interconnected one, because cytokines can induce each other, or each other's receptors, and can enhance or stifle each other's signaling pathways. Further complexity stems from the widespread sharing of JAK kinases by cytokine receptors (e.g., JAK1 is connected to receptors for interferons,

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“…1 Abnormalities in the JAK/STAT signaling pathway lead to many diseases such as immunodeficiency, inflammation, and cancers. 2 Constitutive activations of JAKs are correlated to oncogenesis.…”

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confidence: 99%

Design, Synthesis, and Antitumor Evaluation of 4-Amino-(1H)-pyrazole Derivatives as JAKs Inhibitors

Liang

Zang

Zhu

et al. 2016

ACS Med. Chem. Lett.

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Abnormalities in the JAK/STAT signaling pathway lead to many diseases such as immunodeficiency, inflammation, and cancer. Herein, we designed and synthesized a series of 4-amino-(1H)-pyrazole derivatives as potent JAKs inhibitors for cancer treatment. Results from in vitro protein kinase inhibition experiments indicated that compounds 3a−f and 11b are potent JAKs inhibitors. For example, the IC 50 values of compound 3f against JAK1, JAK2, and JAK3 were 3.4, 2.2, and 3.5 nM, respectively. In cell culture experiments, compound 3f showed potent antiproliferative activity against various cell lines (PC-3, HEL, K562, MCF-7, and MOLT4) at low micromolar levels, while compound 11b showed selective cytotoxicity at submicromolar levels against HEL (IC 50 : 0.35 μM) and K562 (IC 50 : 0.37 μM) cell lines. It is worth noting that both 3f and 11b showed more potent antiproliferative activities than the approved JAKs inhibitor Ruxolitinib. KEYWORDS: JAKs, Inhibitors, 4-Amino-(1H)-pyrazole, Anticancer T he JAK/STAT signaling pathway plays critical roles in immunity, hematopoiesis, and cell growth.1 Abnormalities in the JAK/STAT signaling pathway lead to many diseases such as immunodeficiency, inflammation, and cancers.2 Constitutive activations of JAKs are correlated to oncogenesis. Dysregulation of JAK2 is discovered in patients with myeloproliferative neoplasms and childhood T cell acute lymphoblastic leukemia. 3Several hematologic malignancies including malignant lymphoma and myeloproliferative disorders are associated with mutations of JAK2.4 Some cytokines and growth factors bind to their receptors and then stimulate JAKs for the phosporylation of STAT3, which is a potential target for anticancer therapy. 6 Thus, the JAK/STAT signaling pathway is a promising antitumor target.Inhibitors of JAKs are widely explored for treatment of immunodeficiency, inflammation, and cancer. Among the synthetic JAK inhibitors for the treatment of cancer identified to date (Figure 1), Ruxolitinib (Incyte's Jakafi) was approved by the US Food and Drug Administration (FDA) in 2013 for the treatment of myelofibrosis, a rare bone marrow cancer. Besides, it is in phase III clinical trials for the treatment of metastatic pancreatic cancer and phase II clinical trials for the treatment of multiple myeloma, leukemia, and colon cancer. 7 There are several other JAKs inhibitors in clinical trials for cancer treatment (Figure 1). JAK2 inhibitor AZD1480 can inhibit STAT5 signaling in prostate cancer cells and then effectively inhibit castration-resistant growth of prostate cancer.8 JAK2 inhibitor TG101348 blocks JAK/STAT signaling leading to suppression of proliferation and induction of apoptosis and is used for the treatment of myelofibrosis.9 JAKs inhibitors Momelotinib and

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Discovery and Development of Janus Kinase (JAK) Inhibitors for Inflammatory Diseases

Cited by 490 publications

References 81 publications

JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines

JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines

Network pharmacology of JAK inhibitors

Design, Synthesis, and Antitumor Evaluation of 4-Amino-(1H)-pyrazole Derivatives as JAKs Inhibitors

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