Applying Molecular Modeling to the Design of Innovative, Non-Symmetrical CXCR4 Inhibitors with Potent Anticancer Activity.

The identification of new compounds with potential activity against CXC chemokine receptor type 4 (CXCR4) has been broadly studied, implying several chemical families, particularly AMD3100 derivatives. Molecular modeling has played a pivotal role in the identification of new active compounds. But, has its golden age ended? A virtual library of 450,000 tetraamines of general structure was constructed by using five spacers and 300 diamines, which were obtained from the corresponding commercially available cyclic amines.

Exploring the unexplored chemical space: Rational identification of new Tafenoquine analogs with antimalarial properties.

Patents tend to define a huge chemical space described by the combinatorial nature of Markush structures. However, the optimization of new principal active ingredient is frequently driven by a simple Free Wilson approach. This procedure leads to a highly focused study on the chemical space near a hit compound leaving many unexplored regions that may present highly biological active reservoirs.

Regulation of miRNA expression by α4β1 integrin-dependent multiple myeloma cell adhesion.

The α4β1 integrin regulates the trafficking of multiple myeloma (MM) cells and contributes to MM disease progression. MicroRNAs (miRNAs) can have both tumor suppressor and oncogenic roles and thus are key controllers of tumor evolution, and have been associated with different phases of MM pathogenesis. Using small RNAseq analysis, we show here that α4β1-dependent MM cell adhesion regulates the expression of forty different miRNAs, therefore expanding our current view of the α4β1 involvement in MM cell biology.

The big data era: The usefulness of folksonomy for natural language processing.

Background: A huge amount of clinical data is generated daily and it is usually filed in clinical reports as natural language. Data extraction and further analysis requires reading and manual review of each report, which is a time consuming process. With the aim to test folksonomy to quickly obtain and analyze the information contained in media reports we set up this study.

Cognate RNA-Binding Modes by the Alternative-Splicing Regulator MBNL1 Inferred from Molecular Dynamics.

The muscleblind-like protein family (MBNL) plays a prominent role in the regulation of alternative splicing. Consequently, the loss of MBNL function resulting from sequestration by RNA hairpins triggers the development of a neuromuscular disease called myotonic dystrophy (DM). Despite the sequence and structural similarities between the four zinc-finger domains that form MBNL1, recent studies have revealed that the four binding domains have differentiated splicing activity.

Deconstructing Markush: Improving the R&D Efficiency Using Library Selection in Early Drug Discovery.

Most of the product patents claim a large number of compounds based on a Markush structure. However, the identification and optimization of new principal active ingredients is frequently driven by a simple Free Wilson approach, leading to a highly focused study only involving the chemical space nearby a hit compound. This fact raises the question: do the tested compounds described in patents really reflect the full molecular diversity described in the Markush structure? In this study, we contrast the performance of rational selection to conventional approaches in seven real-case patents, assessing their ability to describe the patent's chemical space.

ICAP-1 loss impairs CD8 thymocyte development and leads to reduced marginal zone B cells in mice.

ICAP-1 regulates β1-integrin activation and cell adhesion. Here, we used ICAP-1-null mice to study ICAP-1 potential involvement during immune cell development and function. Integrin α4β1-dependent adhesion was comparable between ICAP-1-null and control thymocytes, but lack of ICAP-1 caused a defective single-positive (SP) CD8 cell generation, thus, unveiling an ICAP-1 involvement in SP thymocyte development.

1-Pyrazolo[3,4-]pyridines: Synthesis and Biomedical Applications.

Pyrazolo[3,4-]pyridines are a group of heterocyclic compounds presenting two possible tautomeric forms: the 1- and 2-isomers. More than 300,000 1-pyrazolo[3,4-]pyridines have been described which are included in more than 5500 references (2400 patents) up to date. This review will cover the analysis of the diversity of the substituents present at positions N1, C3, C4, C5, and C6, the synthetic methods used for their synthesis, starting from both a preformed pyrazole or pyridine, and the biomedical applications of such compounds.

Expanding the Diversity at the C-4 Position of Pyrido[2,3-]pyrimidin-7(8)-ones to Achieve Biological Activity against ZAP-70.

Pyrido[2,3-]pyrimidin-7(8)-ones have attracted widespread interest due to their similarity with nitrogenous bases found in DNA and RNA and their potential applicability as tyrosine kinase inhibitors. Such structures, presenting up to five diversity centers, have allowed the synthesis of a wide range of differently substituted compounds; however, the diversity at the C4 position has mostly been limited to a few substituents. In this paper, a general synthetic methodology for the synthesis of 4-substituted-2-(phenylamino)-5,6-dihydropyrido[2,3-]pyrimidin-7(8)-ones is described.

1,6-Naphthyridin-2(1)-ones: Synthesis and Biomedical Applications.

Naphthyridines, also known as diazanaphthalenes, are a group of heterocyclic compounds that include six isomeric bicyclic systems containing two pyridine rings. 1,6-Naphthyridines are one of the members of such a family capable of providing ligands for several receptors in the body. Among such structures, 1,6-naphthyridin-2(1)-ones () are a subfamily that includes more than 17,000 compounds (with a single or double bond between C3 and C4) included in more than 1000 references (most of them patents).

Neuronavigated Ultrasound in Neuro-Oncology: A True Real-Time Intraoperative Image.

Objective: Ultrasound is considered a real-time imaging method in neuro-oncology because of its highly rapid image acquisition time. However, to our knowledge, there are no studies that analyze the additional surgical time that it requires.

Methods: A prospective study of 100 patients who underwent intra-axial brain tumor resection with navigated intraoperative ultrasound.

Lenience breeds strictness: The generosity-erosion effect in hiring decisions.

In recruitment processes, candidates are often judged one after another. This sequential procedure affects the outcome of the process. Here, we introduce the generosity-erosion effect, which states that evaluators might be harsher in their assessment of candidates after grading previous candidates generously.

The Role of Tumor Microenvironment in Multiple Myeloma Development and Progression.

Multiple myeloma (MM) is a hematologic cancer characterized by clonal proliferation of plasma cells in the bone marrow (BM). The progression, from the early stages of the disease as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to MM and occasionally extramedullary disease, is drastically affected by the tumor microenvironment (TME). Soluble factors and direct cell-cell interactions regulate MM plasma cell trafficking and homing to the BM niche.

A captured room temperature stable Wheland intermediate as a key structure for the orthogonal decoration of 4-amino-pyrido[2,3-]pyrimidin-7(8)-ones.

Wheland intermediates are usually unstable compounds and only a few have been isolated at very low temperatures. During our work on tyrosine kinase inhibitors, we studied the bromination of 7 in order to obtain a dibromo substituted pyrido[2,3-d]pyrimidin-7(8H)-one which could be orthogonally decorated. Surprisingly, treatment of 7 with 3 equiv.

C4-C5 fused pyrazol-3-amines: when the degree of unsaturation and electronic characteristics of the fused ring controls regioselectivity in Ullmann and acylation reactions.

Pyrazol-3-amine is a scaffold present in a large number of compounds with a wide range of biological activities and, in many cases, the heterocycle is C4-C5 fused to a second ring. Among the different reactions used for the decoration of the pyrazole ring, Ullmann and acylation have been widely applied. However, there is some confusion in the literature regarding the regioselectivity of such reactions (substitution at N1 or N2 of the pyrazole ring) and no predictive rule has been so far established.

Upregulated expression and function of the α4β1 integrin in multiple myeloma cells resistant to bortezomib.

The interaction of multiple myeloma (MM) cells with the bone marrow (BM) microenvironment promotes MM cell retention, survival, and resistance to different anti-MM agents, including proteasome inhibitors (PIs) such as bortezomib (BTZ). The α4β1 integrin is a main adhesion receptor mediating MM cell-stroma interactions and MM cell survival, and its expression and function are downregulated by BTZ, leading to inhibition of cell adhesion-mediated drug resistance (CAM-DR) and MM cell apoptosis. Whether decreased α4β1 expression and activity are maintained or recovered upon development of resistance to BTZ represents an important question, as a potential rescue of α4β1 function could boost MM cell survival and disease progression.

Pyrido[2,3-]pyrimidin-7(8)-ones: Synthesis and Biomedical Applications.

Pyrido[2,3-]pyrimidines () are a type of privileged heterocyclic scaffolds capable of providing ligands for several receptors in the body. Among such structures, our group and others have been particularly interested in pyrido[2,3-]pyrimidine-7(8)-ones () due to the similitude with nitrogen bases present in DNA and RNA. Currently there are more than 20,000 structures described which correspond to around 2900 references (half of them being patents).

Resistance to MAPK Inhibitors in Melanoma Involves Activation of the IGF1R-MEK5-Erk5 Pathway.

Combined treatment of metastatic melanoma with BRAF and MEK inhibitors has improved survival, but the emergence of resistance represents an important clinical challenge. Targeting ERK is a suitable strategy currently being investigated in melanoma and other cancers. To anticipate possible resistance to ERK inhibitors (ERKi), we used SCH772984 (SCH) as a model ERKi to characterize resistance mechanisms in two BRAF V600E melanoma cell lines.

Molecular Players in Hematologic Tumor Cell Trafficking.

The trafficking of neoplastic cells represents a key process that contributes to progression of hematologic malignancies. Diapedesis of neoplastic cells across endothelium and perivascular cells is facilitated by adhesion molecules and chemokines, which act in concert to tightly regulate directional motility. Intravital microscopy provides spatio-temporal views of neoplastic cell trafficking, and is crucial for testing and developing therapies against hematologic cancers.

Application of a Thrombin-Gelatin Matrix in the Management of Intractable Hemorrhage During Stereotactic Biopsy.

Background: Few studies have been published about percutaneous techniques for management of surgical bed hemorrhage during a stereotactic biopsy, a serious complication that may affect patient outcome. We describe the injection of a thrombin-gelatin matrix through the biopsy cannula as an effective method to arrest surgical bed bleeding that does not respond to conventional methods of hemostasis.

Methods: We prospectively documented image-guided stereotactic brain biopsy procedures in 30 awake patients between July 2014 and July 2017 at our center.

Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma.

Constitutive activation of the chemokine receptor CXCR4 has been associated with tumor progression, invasion, and chemotherapy resistance in different cancer subtypes. Although the CXCR4 pathway has recently been suggested as an adverse prognostic marker in diffuse large B-cell lymphoma, its biological relevance in this disease remains underexplored. In a homogeneous set of 52 biopsies from patients, an antibody-based cytokine array showed that tissue levels of CXCL12 correlated with high microvessel density and bone marrow involvement at diagnosis, supporting a role for the CXCL12-CXCR4 axis in disease progression.

The good and bad faces of the CXCR4 chemokine receptor.

Chemokines are chemotactic cytokines that promote cell migration and activation under homeostatic and inflammatory conditions. Chemokines bind to seven transmembrane-spanning receptors that are coupled to heterotrimeric guanine nucleotide-binding (G) proteins, which are the responsible for intracellularly transmitting the activating signals for cell migration. Hematopoiesis, vascular development, lymphoid organ morphogenesis, cardiogenesis and neural differentiation are amongst the processes involving chemokine function.