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In this study, we aimed to develop a pharmacophore-based three-dimensional quantitative structure activity relationship (3D-QSAR) for a set including sixty-two cytotoxic quinolines (1-62) as anticancer agents with tubulin inhibitory activity. A total of 279 pharmacophore hypotheses were generated based on the survival score to build QSAR models. A six-point pharmacophore model (AAARRR.1061) was identified as the best model which consisted of three hydrogen bond acceptors (A) and three aromatic ring (R) features. The model showed a high correlation coefficient (R2=0.865), cross-validation coefficient (Q2=0.718), and F value (72.3). The best pharmacophore model was then validated by the Y-Randomization test and ROC-AUC analysis. The generated 3D contour maps were used to reveal the structure activity relationship of the compounds. The IBScreen database was screened against AAARRR.1061, and after calculating ADMET properties, 10 compounds were selected for further docking study. Molecular docking analysis showed that compound STOCK2S-23597 with the highest docking score (-10.948 kcal/mol) had hydrophobic interactions and can form four hydrogen bonds with active site residues.

Gastric cancer (GC) is the third cause of cancer-related death worldwide. Patients with unresectable GC can be treated with chemotherapy such as paclitaxel, which is a microtubule stabilizer. The use of nanoparticle albumin-bound paclitaxel (nab-ptx) avoids hypersensitivity reactions due to the absence of solvent needed to dissolve paclitaxel and it can be administered at higher doses. The ABSOLUTE randomized phase-3 clinical trial showed the non-inferiority of the nab-ptx used every week compared to the solvent-based paclitaxel used every week. This review describes the current advancements of the use of nab-ptx in GC in preclinical and clinical study investigations. The possibility of combining nab-ptx with other medications to improve response of patients to their specific molecular needs will also be debated.

Aim We investigated the efficacy and safety of using paclitaxel-coated balloon (PCB) to treat small vessel disease. Methods and results In this multicenter, prospective, randomized controlled trial, one-hundred and thirty-five patients with native coronary lesions in small vessels were randomized into a PCB group and plain balloon angioplasty (POBA) group at a ratio of 2:1. There were no differences in target vessel failure (TVF) that was defined as cardiac death or target vessel-related myocardial infarction or target lesion revascularization (TLR), between the two groups (3.4 vs. 10.3%; P  = 0.20), and TLR was slightly lower in the PCB group (2.3%) than that in the POBA group (10.3%) during 24 weeks follow-up. The late lumen loss (LLL) was significantly lower in the PCB group (0.01 ± 0.31 vs. 0.32 ± 0.34 mm; P  < 0.01) and late lumen enlargement (LLE) was more frequently observed in the PCB group (48 vs. 15%; P  < 0.01) by angiographic follow-up after 24 weeks. There were no cases of death, myocardial infarction, thrombosis and reocclusion in either group. Conclusions This study was not able to demonstrate superiority of PCB compared with POBA.

Stathmin1 (STMN1) is a microtubule modulator that is expressed in multiple cancers and correlates with poor survival. We previously demonstrated in vivo safety of bifunctional (bi) shRNA STMN1 bilamellar invaginated vesicle (BIV) and that systemic delivery correlated with antitumor activity. Patients with superficial advanced refractory cancer with no other standard options were entered into trial. Study design involved dose escalation (four patients/cohort) using a modified Fibonacci schema starting at 0.7 mg DNA administered via single intratumoral injection. Biopsy at baseline, 24/48 hours and resection 8 days after injection provided tissue for determination of cleavage product using next-generation sequencing (NGS) and reverse transcription quantitative polymerase chain reaction (RT-qPCR), 5′ RLM rapid amplification of cDNA ends (RACE) assay. Serum pharmacokinetics of circulating plasmid was done. Twelve patients were entered into three dose levels (0.7, 1.4, 7.0 mg DNA). No ≥ grade 3 toxic effects to drug were observed. Maximum circulating plasmid was detected at 30 seconds with less than 10% detectable in all subjects at 24 hours. No toxic effects were observed. Predicted cleavage product was detected by both NGS (n = 7/7 patients analyzed, cohorts 1, 2) and RLM RACE (n = 1/1 patients analyzed cohort 3). In conclusion, bi-shRNA STMN1 BIV is well tolerated and detection of mRNA target sequence-specific cleavage product confirmed bi-shRNA BIV mechanism of action.

Tubulin-targeted chemotherapy has proven to be a successful and wide spectrum strategy against solid and liquidmalignancies. Therefore, new ways to modulate this essential protein could lead to new antitumoral pharmacological approaches. Currently known tubulin agents bind to six distinct sites at α/β-tubulin either promoting microtubule stabilization or depolymerization. We have discovered a seventh binding site at the tubulin intradimer interface where a novel microtubule-destabilizing cyclodepsipeptide, termed gatorbulin-1 (GB1), binds. GB1 has a unique chemotype produced by a marine cyanobacterium. We have elucidated this dual, chemical and mechanistic, novelty through multidimensional characterization, starting with bioactivity-guided natural product isolation and multinuclei NMR-based structure determination, revealing the modified pentapeptide with a functionally critical hydroxamate group; and validation by total synthesis. We have investigated the pharmacology using isogenic cancer cell screening, cellular profiling, and complementary phenotypic assays, and unveiled the underlying molecular mechanism by in vitro biochemical studies and high-resolution structural determination of the α/β-tubulin–GB1 complex.

Eukaryotic cells rely on long-lived microtubules for intracellular transport and as compression-bearing elements. We considered that long-lived microtubules are acetylated inside their lumen and that microtubule acetylation may modify microtubule mechanics. Here, we found that tubulin acetylation is required for the mechanical stabilization of long-lived microtubules in cells. Depletion of the tubulin acetyltransferase TAT1 led to a significant increase in the frequency of microtubule breakage. Nocodazole-resistant microtubules lost upon removal of acetylation were largely restored by either pharmacological or physical removal of compressive forces. In in vitro reconstitution experiments, acetylation was sufficient to protect microtubules from mechanical breakage. Thus, acetylation increases mechanical resilience to ensure the persistence of long-lived microtubules.

Key Points Microtubule organization and dynamics are controlled by proteins that associate with the two microtubule extremities, the plus end and the minus end. Proteins accumulating at microtubule ends can promote or inhibit microtubule polymerization, enhance or block microtubule disassembly, or induce transitions between microtubule growth and shortening. Microtubule plus-end-tracking proteins (+TIPs) can accumulate at microtubule ends by recognizing the stabilizing GTP cap at growing microtubule tips or the curvature of the outermost part of the microtubule, or by plus-end-directed motor activity. This accumulation can be enhanced by electrostatic interactions between positively charged protein domains and the negatively charged microtubule lattice. +TIPs form extensive interaction networks, which depend on a limited number of protein motifs and modules that bind to each other with moderate affinity, allowing rapid remodelling of the end-associated complexes during microtubule growth and shortening. The recruitment of proteins with SxIP and cytoskeleton-associated protein Gly-rich (CAP-Gly) domains by the 'autonomous' +TIPs of the end-binding protein (EB) family plays a major part in the formation of these networks. +TIP networks are responsible for a large range of cellular functions, such as microtubule guidance along other cytoskeletal elements, microtubule attachment to the cell cortex, kinetochores and intracellular membrane organelles, positioning of microtubule arrays and signalling. Microtubule minus-end-targeting proteins (−TIPs) of the calmodulin-regulated spectrin-associated protein (CAMSAP) and Patronin family accumulate at free, growing microtubule minus ends and control the architecture of microtubule networks by stabilizing non-centrosomal microtubules. A wide range of diverse pharmacological agents can target microtubule tips either directly or indirectly and cooperate with +TIPs in regulating the dynamics of microtubule ends. Microtubule plus ends and minus ends accumulate specific sets of proteins that can regulate microtubule dynamics, connect microtubules to cellular structures and recruit signalling molecules that collectively control cellular behaviour. Our knowledge of the factors that associate with microtubule ends, and the mechanisms through which they do this, has strongly increased in recent years. Microtubules have fundamental roles in many essential biological processes, including cell division and intracellular transport. They assemble and disassemble from their two ends, denoted the plus end and the minus end. Significant advances have been made in our understanding of microtubule plus-end-tracking proteins (+TIPs) such as end-binding protein 1 (EB1), XMAP215, selected kinesins and dynein. By contrast, information on microtubule minus-end-targeting proteins (−TIPs), such as the calmodulin-regulated spectrin-associated proteins (CAMSAPs) and Patronin, has only recently started to emerge. Here, we review our current knowledge of factors, including microtubule-targeting agents, that associate with microtubule ends to control the dynamics and function of microtubules during the cell cycle and development.

Tubulin dynamics is a promising target for new chemotherapeutic agents. The colchicine binding site is one of the most important pockets for potential tubulin polymerization destabilizers. Colchicine binding site inhibitors (CBSI) exert their biological effects by inhibiting tubulin assembly and suppressing microtubule formation. A large number of molecules interacting with the colchicine binding site have been designed and synthesized with significant structural diversity. CBSIs have been modified as to chemical structure as well as pharmacokinetic properties, and tested in order to find a highly potent, low toxicity agent for treatment of cancers. CBSIs are believed to act by a common mechanism via binding to the colchicine site on tubulin. The present review is a synopsis of compounds that have been reported in the past decade that have provided an increase in our understanding of the actions of CBSIs.

Microtubule dynamics and their control are essential for the normal function and division of all eukaryotic cells. This plethora of functions is, in large part, supported by dynamic microtubule tips, which can bind to various intracellular targets, generate mechanical forces and couple with actin microfilaments. Here, we review progress in the understanding of microtubule assembly and dynamics, focusing on new information about the structure of microtubule tips. First, we discuss evidence for the widely accepted GTP cap model of microtubule dynamics. Next, we address microtubule dynamic instability in the context of structural information about assembly intermediates at microtubule tips. Three currently discussed models of microtubule assembly and dynamics are reviewed. These are considered in the context of established facts and recent data, which suggest that some long-held views must be re-evaluated. Finally, we review structural observations about the tips of microtubules in cells and describe their implications for understanding the mechanisms of microtubule regulation by associated proteins, by mechanical forces and by microtubule-targeting drugs, prominently including cancer chemotherapeutics.In cells, microtubules are dynamically assembled and disassembled at their growing (plus) tips. Recent insights into microtubule plus tip organization now pave the way for understanding the regulation of microtubule dynamics and for addressing how these dynamics allow microtubules to fulfil their vast repertoire of cellular functions.

The auristatin class of microtubule destabilizers are highly potent cytotoxic agents against several cancer cell types when delivered as antibody drug conjugates. Here we describe the high resolution structures of tubulin in complex with both monomethyl auristatin E and F and unambiguously define the trans-configuration of both ligands at the Val-Dil amide bond in their tubulin bound state. Moreover, we illustrate how peptidic vinca-site agents carrying terminal carboxylate residues may exploit an observed extended hydrogen bond network with the M-loop Arg278 to greatly improve the affinity of the corresponding analogs and to maintain the M-loop in an incompatible conformation for productive lateral tubulin-tubulin contacts in microtubules. Our results highlight a potential, previously undescribed molecular mechanism by which peptidic vinca-site agents maintain unparalleled potency as microtubule-destabilizing agents.