Lenalidomide is the first karyotype-selective therapeutic approved for treatment of myelodysplastic syndromes (MDS) owing to high rates erythroid and cytogenetic response in patients with chromosome 5q deletion [del(5q)]. Although haploinsufficiency RPS14 gene others encoded within common deleted region (CDR) have been implicated pathogenesis del(5q) phenotype, molecular basis karyotype specificity lenalidomide remains unexplained. We focused our analysis on possible haplodeficient enzymatic...

Abstract The Rho-associated kinases ROCK1 and ROCK2 are critical for cancer cell migration invasion, suggesting they may be useful therapeutic targets. In this study, we describe the discovery development of RKI-1447, a potent small molecule inhibitor ROCK2. Crystal structures RKI-1447/ROCK1 complex revealed that RKI-1447 is Type I kinase binds ATP binding site through interactions with hinge region DFG motif. suppressed phosphorylation ROCK substrates MLC-2 MYPT-1 in human cells, but had no...

STAT3-STAT3 dimerization, which involves reciprocal binding of the STAT3-SH2 domain to phosphorylated tyrosine-705 (Y-705), is required for STAT3 nuclear translocation, DNA binding, and transcriptional regulation downstream target genes. Here, we describe a small molecule S3I-1757 capable disrupting activation, malignant transforming activity. Fluorescence polarization assay molecular modeling suggest that interacts with phospho-Y-705-binding site in SH2 displaces fluorescein-labeled...

Screening of the NCI diversity set compounds has led to identification 5 (NSC-117199), which inhibits protein tyrosine phosphatase (PTP) Shp2 with an IC50 47 μM. A focused library incorporating isatin scaffold was designed and evaluated for inhibition Shp1 PTP activities. Several were identified that selectively inhibit over PTP1B low submicromolar activity. model binding active is proposed.

The o-carboxylic acid substituted bisanilinopyrimidine 1 was identified as a potent hit (Aurora A IC50 = 6.1 ± 1.0 nM) from in-house screening. Detailed structure–activity relationship (SAR) studies indicated that polar substituents at the para position of B-ring are critical for activity. X-ray crystallography revealed compound is type I inhibitor binds Aurora kinase active site in DFG-in conformation. Structure–activity guided replacement A-ring carboxylic with halogens and incorporation...

Most protein kinases share a DFG (Asp-Phe-Gly) motif in the ATP site that can assume two distinct conformations, active DFG-in and inactive DFG-out states. Small molecule inhibitors able to induce state have received considerable attention kinase drug discovery. Using typical inhibitor scaffold of Aurora A, involved regulation cell division, we found halogen nitrile substituents directed at N-terminally flanking residue Ala273 induced global conformational changes enzyme, leading are among...

Using high concentration biochemical assays and fragment-based screening assisted by structure-guided design, we discovered a novel class of Rho-kinase inhibitors. Compound 18 was equipotent for ROCK1 (IC(50) = 650 nM) ROCK2 670 nM), whereas compound 24 more selective 100 over 1690 nM). The crystal structure the 18-ROCK1 complex revealed that is type 1 inhibitor binds hinge region in ATP binding site. Compounds inhibited potently phosphorylation ROCK substrate MLC2 intact human breast cancer cells.

Potent ROCK inhibitors of a new class 1-benzyl-3-(4-pyridylthiazol-2-yl)ureas have been identified. Remarkable differences in activity were observed for ureas bearing benzylic stereogenic center. Derivatives with hydroxy, methoxy and amino groups at the meta position phenyl ring give rise to most potent (low nM). Substitutions para result substantial loss potency. Changes are tolerated resulting significant potency case methyl methylenehydroxy groups. X-Ray crystallography was used establish...

The O-tosylsalicylamide S3I-201 (10) was used as a starting point for design and synthesis of novel STAT-3 dimerization inhibitors with improved drug-like qualities. phosphonic acid 12d salicylic acids 13f, 13g shorter amide linker lacking the O-tosyl group had inhibitory activity. equivalent potencies observed by replacement moiety 5-amino-2-hydroxybenzoic in 13f further validates phosphotyrosine mimic. displayed whole cell focused library 13 benzamide indicated that hydrophobic heptyl...

Abstract Metastatic melanoma is an aggressive cancer with very low response rate against conventional chemotherapeutic agents such as dacarbazine (DTIC). Inhibitor of Rb–Raf-1 interaction RRD-251 was tested the cell lines SK-MEL-28, SK-MEL-5, and SK-MEL-2. found to be a potent inhibitor proliferation, irrespective V600E B-Raf mutation status lines. In SK-MEL-28 xenograft experiment, exerted significant suppression tumor growth compared vehicle (P = 0.003). Similar in vitro effects, tumors...

Abstract Issue/problem The international and scientific community has been calling for many years to strengthen prevention preparedness threats at the human-animal-environment interface by integrating a systemic approach, such One Health (OH). Furthermore, COVID-19 pandemic highlighted importance of OH enhance health security. However, national level, governments are delaying integration in their public systems or plans. Description problem WHO Regional Office Europe is supporting...

Abstract Rho GTPase is a small G-protein which plays critical role in signaling pathways and controls cell growth division. Rho-associated protein kinase (known as ROCK or kinase) Ser/Thr activated by GTP-bound phosphorylates target proteins involved various signal transduction pathways. the Rho-kinase signalling are implicated morphology, motility, smooth muscle contraction, formation of stress fibres, focal adhesion transformation. ROCKs have been subject to growing attention, having range...

Over the past decade, emergence of Massive Online Open Courses (MOOCs) has profoundly transformed distance learning landscape, capturing attention both higher education and professional institutions. This surge interest not only spurred development innovative teaching methods but also led to a re-evaluation content production reuse strategies. In fact, when producing MOOCs, multiple resources efforts are dedicated creating considerable amount material. is often housed within environment,...

In the Horizon 2020 project inDICEs, a consortium of 14 interdisciplinary partners from research and industry set out to develop an approach on how understand measure impact digital cultural heritage. Synthesising results three years research, produced MOOC KULeuvenX edX platform, focused development transition strategies for both non-profit business models in heritage institutions as well broader creative industries. Built KU Leuven’s experience developing MOOCs derived this particular...

Abstract Aurora kinases belong to the serine/threonine subclass of involved in regulation mitosis. Out three isoforms kinases; A, B and C, studies have shown A are up-regulated many cancers including breast colorectal cancers. Deregulated kinase activity has been linked genetic instability, defects centrosome function, spindle assembly, chromosome alignment cytokinesis, all which can lead tumorigenesis. Inhibition is emerging as target-based therapy cancer treatment. HLM-8598 was identified...

Abstract The ability of STAT3 to translocate the nucleus, bind DNA and transcriptionally regulate target genes depends on tyrosine phosphorylation STAT3-STAT3 dimerization. Our chemistry efforts led discovery S3I-1757 that disrupts Fluorescence polarization assays molecular modeling show interacts with Y-705 binding site in STAT3-SH2 domain displaces fluorescein-labelled GpYLPQTV phosphotyrosine peptide from STAT3. Furthermore, using co-immunoprecipitation co-localization studies we inhibits...

Abstract The association of aberrant STAT3 activation with many types human malignancies and solid tumors makes an attractive molecular target for the development novel cancer therapeutics. dimerization via two reciprocal phosphotyrosine (pTyr)-Src-homology 2 (SH2) interaction is required its binding to specific DNA-response elements in promoters genes. This process offers a potentially selective way directly STAT3. Nevertheless design small molecules capable disrupting protein-protein...

Abstract Rho associated protein kinases (ROCKs) are Ser/Thr which require activation by small GTPases of the family. ROCK is often found to be over expressed in ovarian, testicular, bladder, and pancreatic cancers. has been implicated cell motility, adhesion, smooth muscle contraction stress fiber formation. Inhibition kinase a novel approach for treatment cardiovascular disease, CNS disorders, and, more recently, cancer. received increased attention its affect on adhesion invasion, two key...

Abstract The M-phase of cell division is controlled by phosphorylation events performed several mitotic serine/threonine kinases. For example, the three human isoforms Aurora kinase (A, B, and C) have been amply investigated as they are essential for execution numerous required genome integrity stability. Studies shown that A B frequently over-expressed in various cancer cells. also acts an oncogene inducing malignant transformation when over-expressed. Since discovery kinases their...

Abstract Using high concentration biochemical assays and fragment-based screening, we designed optimized a novel class of Rho-kinase inhibitors. Ligand Efficiency (LE) was employed to assess the binding potential fragments guide optimization process. In addition, molecular modeling used aide design potent A series as hinge binders were synthesized, screened using assays. Both spacer length isomeric tail molecules played key roles in both activity selectivity. Structure relationship studies...

Abstract Retinoblastoma tumor suppressor binding protein, Rb, is a major regulator of the mammalian cell cycle progression. Inactivation Rb by cascade phosphorylation events leads to its inactivation, facilitating release transcriptionally active E2F and S-phase entry. phosphorylaiton mediated mainly CDK, but it was observed Raf-1 could bind phosphorylate early in cycle, events. Although previous reports have suggested that K-Ras, which mutated over 80% pancreatic cancers, activates MAPK...