TYK2 is a JAK family protein tyrosine kinase activated in response to multiple cytokines, including type I IFNs, IL-6, IL-10, IL-12, and IL-23. Extensive studies of mice that lack TYK2 expression ...indicate that the IFN-α, IL-12, and IL-23 pathways, but not the IL-6 or IL-10 pathways, are compromised. In contrast, there have been few studies of the role of TYK2 in primary human cells. A genetic mutation at the tyk2 locus that results in a lack of TYK2 protein in a single human patient has been linked to defects in the IFN-α, IL-6, IL-10, IL-12, and IL-23 pathways, suggesting a broad role for TYK2 protein in human cytokine responses. In this article, we have used a panel of novel potent TYK2 small-molecule inhibitors with varying degrees of selectivity against other JAK kinases to address the requirement for TYK2 catalytic activity in cytokine pathways in primary human cells. Our results indicate that the biological processes that require TYK2 catalytic function in humans are restricted to the IL-12 and IL-23 pathways, and suggest that inhibition of TYK2 catalytic activity may be an efficacious approach for the treatment of select autoimmune diseases without broad immunosuppression.
A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as psoriasis and inflammatory bowel diseases (IBD), by selective targeting of TYK2. Hit triage, following a ...high-throughput screen for TYK2 inhibitors, revealed pyridine 1 as a promising starting point for lead identification. Initial expansion of 3 separate regions of the molecule led to eventual identification of cyclopropyl amide 46, a potent lead analog with good kinase selectivity, physicochemical properties, and pharmacokinetic profile. Analysis of the binding modes of the series in TYK2 and JAK2 crystal structures revealed key interactions leading to good TYK2 potency and design options for future optimization of selectivity.
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•Biological rationale for targeting selective TYK2 inhibition is given.•We report lead identification of potent and efficient TYK2 inhibitors.•Analogs afford modest selectivity against other Janus Family kinases.•We obtained crystal structures of key compounds bound to both TYK2 and JAK2.•ADME properties of the lead compound are favorable.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these ...disorders. A high-throughput screening effort identified the pyrazolo1,5-apyrimidine scaffold as a potent inhibitor of Jak2. Optimization of lead compounds 7a–b and 8 in this chemical series for activity against Jak2, selectivity against other Jak family kinases, and good in vivo pharmacokinetic properties led to the discovery of 7j. In a SET2 xenograft model that is dependent on Jak2 for growth, 7j demonstrated a time-dependent knock-down of pSTAT5, a downstream target of Jak2.
Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover ...2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.
The Rho GTPases mediate actin rearrangements that are likely to be required for the numerous cell shape changes in a developing embryo. In a genetic screen for Rho signaling pathway components in ...Drosophila, we identified a gene,
DRhoGEF2, that encodes a predicted Rho-specific guanine nucleotide exchange factor. Embryos lacking DRhoGEF2 fail to gastrulate due to a defect in cell shape changes required for tissue invagination, and expression of a dominant-negative Rho GTPase in early embryos results in similar defects. Evidence is also presented that DRhoGEF2 mediates these specific cell shape changes in response to the extracellular ligand, Fog. Together, these results establish a Rho-mediated signaling pathway that is essential for the major morphogenetic events in Drosophila gastrulation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract A new finite element model is proposed for the analysis of the mechanical aspects of morphogenesis and tested on the biologically well studied gastrulation phenomenon, in particular ventral ...furrow invagination of the Drosophila melanogaster embryo. A set of mechanisms are introduced in the numerical model, which lead to the observed deformed shapes. We split the total deformation into two parts: an imposed active deformation, and an elastic deformation superimposed onto the latter. The active deformation simulates the effects of apical constriction and apico-basal elongation. These mechanisms are associated with known gene expressions and so in this way we attempt to bridge the well explored signalling pathways, and their associated phenotypes in a mechanical model. While the former have been studied in depth, much less can be said about the forces they produce and the mechanisms involved. From the numerical results, we are able to test different plausible mechanical hypotheses that generate the necessary folding observed in the invagination process. In particular, we conclude that only certain ratios between both modes (apical constriction and apico-basal elongation) can successfully reproduce the invagination process. The model also supports the idea that this invagination requires the contribution of several mechanisms, and that their redundancy provides the necessary robustness.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Sculpting Idolatry in Flavian Rome: (An)Iconic Rhetoric in the Writings of Flavius Josephus. By Jason von Ehrenkrook. Early Judaism and Its Literature, vol. 33. Atlanta: Society of Biblical ...Literature, 2011. Pp. xiv + 226. $29.95 (paper).
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Rac and Cdc42 GTPases share several regulators and effectors, yet perform distinct biological functions. The factors determining such specificity in vivo have not been identified. In a mutational ...screen in Drosophila to identify Rac-specific signaling components, we isolated 11 alleles of myoblast city (mbc). mbc mutant embryos exhibit defects in dorsal closure, myogenesis, and neural development. DOCK180, the mammalian homolog of Mbc, associates with Rac, but not Cdc42, in a nucleotide-independent manner. These results suggest that Mbc is a specific upstream regulator of Rac activity that mediates several morphogenetic processes in Drosophila embryogenesis.
We report the SAR studies of a series of structurally novel benzotriazine analogs as inhibitors of Src. The 3-(2-(1-pyrrolidinyl)-ethoxy)phenyl analog (
43) was identified as one of the most potent ...inhibitors.
We report the discovery and preliminary SAR studies of a series of structurally novel benzotriazine core based small molecules as inhibitors of Src kinase. To the best of our knowledge, benzotriazine template based compounds have not been reported as kinase inhibitors. The 3-(2-(1-pyrrolidinyl)ethoxy)phenyl analogue (
43) was identified as one of the most potent inhibitors of Src kinase.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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