SB1518 is an innovative pyrimidine-based macrocycle that shows a unique kinase profile with selective inhibition of Janus Kinase-2 (JAK2; IC50=23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) ...within the JAK family (IC50=1280, 520 and 50 nM for JAK1, JK3 and TYK2, respectively) and fms-like tyrosine kinase-3 (FLT3; IC50=22 nM). SB1518 shows potent effects on cellular JAK/STAT pathways, inhibiting tyrosine phosphorylation on JAK2 (Y221) and downstream STATs. As a consequence SB1518 has potent anti-proliferative effects on myeloid and lymphoid cell lines driven by mutant or wild-type JAK2 or FLT3, resulting from cell cycle arrest and induction of apoptosis. SB1518 has favorable pharmacokinetic properties after oral dosing in mice, is well tolerated and significantly reduces splenomegaly and hepatomegaly in a JAK2(V617F)-driven disease model. SB1518 dose-dependently inhibits intra-tumor JAK2/STAT5 signaling, leading to tumor growth inhibition in a subcutaneous model generated with SET-2 cells derived from a JAK2(V617F) patient with megakaryoblastic leukemia. Moreover, SB1518 is active against primary erythroid progenitor cells sampled from patients with myeloproliferative disease. In summary, SB1518 has a unique profile and is efficacious and well tolerated in JAK2-dependent models. These favorable properties are now being confirmed in clinical studies in patients with myelofibrosis and lymphoma.
This review describes the possibilities of using templates to create organic polymer networks with new architectures and functionalities. Examples are given for the whole range of templates starting ...from functional organic molecules (molecular imprinting) to organized arrays of solid colloids (colloidal imprinting) up to micelles, microemulsions and lyotropic phases (self-organized templates), whereas classical thermodynamic techniques like addition of structural cosolvents or gelation during precipitation polymerization, are not considered. Also some examples for potential applications of the discussed porous polymer gels are presented.
The potassium ionophore nigericin induces cell death and promotes the maturation and release of IL-1beta in lipopolysaccharide (LPS)-primed monocytes and macrophages, the latter depending on ...caspase-1 activation by an unknown mechanism. Here, we investigate the pathway that triggers cell death and activates caspase-1. We show that without LPS priming, nigericin alone triggered caspase-1 activation and IL-18 generation in THP-1 monocytic cells. Simultaneously, nigericin induced caspase-1-independent necrotic cell death, which was blocked by the cathepsin B inhibitor CA-074-Me and other cathepsin inhibitors. Cathepsin B activation after nigericin treatment was determined biochemically and corroborated by rapid lysosomal leakage and translocation of cathepsin B to the cytoplasm. IL-18 maturation was prevented by both caspase-1 and cathepsin B inhibitors in THP-1 cells, primary mouse macrophages and human blood monocytes. Moreover, IL-18 generation was reduced in THP-1 cells stably transformed either with cystatin A (an endogenous cathepsin inhibitor) or antisense cathepsin B cDNA. Collectively, our study establishes a critical role for cathepsin B in nigericin-induced caspase-1-dependent IL-18 maturation and caspase-1-independent necrosis.
Acute myeloid leukemia (AML) is currently treated with aggressive chemotherapy that is not well tolerated in many elderly patients, hence the unmet medical need for effective therapies with less ...toxicity and better tolerability. Inhibitors of FMS-like tyrosine kinase 3 (FLT3), JAK2 and histone deacetylase inhibitors (HDACi) have been tested in clinical studies, but showed only moderate single-agent activity. High efficacy of the HDACi pracinostat treating AML and synergy with the JAK2/FLT3 inhibitor pacritinib is demonstrated. Both compounds inhibit JAK-signal transducer and activator of transcription (STAT) signaling in AML cells with JAK2(V617F) mutations, but also diminish FLT3 signaling, particularly in FLT3-ITD (internal tandem duplication) cell lines. In vitro, this combination led to decreased cell proliferation and increased apoptosis. The synergy translated in vivo in two different AML models, the SET-2 megakaryoblastic AML mouse model carrying a JAK2(V617F) mutation, and the MOLM-13 model of FLT3-ITD-driven AML. Pracinostat and pacritinib in combination showed synergy on tumor growth, reduction of metastases and synergistically decreased JAK2 or FLT signaling, depending on the cellular context. In addition, several plasma cytokines/growth factors/chemokines triggered by the tumor growth were normalized, providing a rationale for combination therapy with an HDACi and a JAK2/FLT3 inhibitor for the treatment of AML patients, particularly those with FLT3 or JAK2 mutations.
Lyotropic phase morphologies of amphiphilic poly(butadiene-b-ethylene oxide) (PB−PEO) block copolymers are studied using transmission electron microscopy, small-angle X-ray scattering, small-angle ...neutron scattering, and polarized optical microscopy. The PB−PEO block copolymers form type-1 lyotropic phases comprising disordered micellar solutions (L1), spheres arranged on a bcc lattice (I1), hexagonally packed cylinders (H1), and lamellae (Lα). Increasing molecular weight destabilizes the I1 and H1 phases and lowers the degree of order. For high molecular weight block copolymers the increase in chain conformational entropy leads to the formation of the sponge phase (L3). The transmission electron micrographs allow a detailed analysis of packing defects and epitaxial relations of the block copolymer lyotropic phases.
Self-organized surfactant solutions, such as microemulsions, vesicular solutions or dispersions, or lyotropic mesophases can serve as templates for the structure directed synthesis of organic ...polymers. Recent developments of templating within these equilibrium nanostructured fluids are reviewed. Depending on the template structure and the reaction conditions, the outcomes may be polyampholytes, amphiphiles, nanoparticles, hollow spheres, or mesoporous polymers. For each structure and morphology, the final product materials reflect a delicate balance between phase behavior and the reaction and mass transfer parameters that set structure. Experimental and theoretical aspects of reaction kinetics and thermodynamics such as monomer partitioning, swelling behavior and polymerization-induced phase separation are discussed.
This review describes conventional and modern techniques of porous organic polymer synthesis. A huge variety of polymer architectures and functions can be gained by foaming, phase separation, ...imprinting or templating approaches. Several applications of porous polymers are discussed, focusing on biotechnological and biomedical applications, such as chromatography, protein synthesis, drug carrier systems, tissue engineering and others.
3D inorganic monoliths with sponge‐like texture have been produced using polymer–gel templates. Colloidal suspensions of magnetite or titanium dioxide nanoparticles were diffused into swellable gels ...(see Figure) composed of acrylic acid–based copolymers, and possessing 3D channels. Hybrid composites were produced that could be subsequently transformed into ceramic monoliths with macroporous structure.
A magnetic mineral–polymer composite consisting of an elastic polystyrene–polyacrylate copolymer gel (see Figure) infiltrated with a magnetic iron oxide nanocolloid is reported to have been prepared ...by a room‐temperature synthesis. This is an example of a biomimetic approach to synthetic analogues of mineral–polymer composites produced by natural organisms.
Recent developments in the identification, in vitro culture and differentiation of stem cells point to the unprecedented potential of these cells, or their derivatives, to cure degenerative ...disorders. Human embryonic stem cells (hESC) offer the particular advantage of prolonged proliferative capacity and great versatility in the lineages that can be formed in culture. Translating these advantages into clinical benefits faces many challenges, including efficient differentiation into the desired cell type(s), maintaining genetic stability during long-term culture and, finally, ensuring the absence of potentially tumorigenic hESC from the final product. It is this final safety issue that will form the focus of this review.
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