Quabodepistat (OPC-167832), a Novel Antituberculosis Drug Candidate: Enhancing Oral Bioavailability via Cocrystallization and Mechanistic Analysis of Bioavailability in Two Cocrystals.

Quabodepistat (code name OPC-167832) is a novel antituberculosis drug candidate. This study aimed to discover cocrystals that improve oral bioavailability and to elucidate the mechanistic differences underlying the bioavailability of different cocrystals. Screening yielded two cocrystals containing 2,5-dihydroxybenzoic acid (2,5DHBA) or 2-hydroxybenzoic acid (2HBA). In bioavailability studies in beagle dogs, both cocrystals exhibited better bioavailability than the free form; however, the extent of bioavailability of cocrystals with 2HBA (quabodepistat-2HBA) was 1.4-fold greater than that of cocrystals with 2,5DHBA (quabodepistat-2,5DHBA). Dissolution studies at pH 1.2 yielded similar profiles for both cocrystals, although the percent dissolution differed: quabodepistat-2HBA dissolved more slowly than quabodepistat-2,5DHBA. The poor solubility of quabodepistat-2HBA is likely the primary factor limiting dissolution at pH 1.2. To identify a dissolution method that maintains the bioavailability in beagle dogs, we performed pH-shift dissolution studies that mimic the dynamic pH change from the stomach to the small intestine. Quabodepistat-2HBA demonstrated supersaturation after the pH was increased to 6.8, while quabodepistat-2,5DHBA did not demonstrate supersaturation. This result was consistent with the results of bioavailability studies in beagle dogs. We conclude that a larger quantity of orally administered quabodepistat-2HBA remained in its cocrystal form while being transferred to the small intestine compared with quabodepistat-2,5DHBA.

Antibody drug conjugates beyond cytotoxic payloads.

For many years, antibody drug conjugates (ADC) have teased with the promise of targeted payload delivery to diseased cells, embracing the targeting of the antibody to which a cytotoxic payload is conjugated. During the past decade this promise has started to be realised with the approval of more than a dozen ADCs for the treatment of various cancers. Of these ADCs, brentuximab vedotin really laid the foundations of a template for a successful ADC with lysosomal payload release from a cleavable dipeptide linker, measured DAR by conjugation to the Cys-Cys interchain bonds of the antibody and a cytotoxic payload. Using this ADC design model oncology has now expanded their repertoire of payloads to include non-cytotoxic compounds. These new payload classes have their origins in prior medicinal chemistry programmes aiming to design selective oral small molecule drugs. While this may not have been achieved, the resulting compounds provide excellent starting points for ADC programmes with some compounds amenable to immediate linker attachment while for others extensive SAR and structural information offer invaluable design insights. Many of these new oncology payload classes are of interest to other therapeutic areas facilitating rapid access to drug-linkers for exploration as non-oncology ADCs. Other therapeutic areas have also pursued unique payload classes with glucocorticoid receptor modulators (GRM) being the most clinically advanced in immunology. Here, ADC payloads come full circle, as oncology is now investigating GRM payloads for the treatment of cancer. This chapter aims to cover all these new ADC approaches while describing the medicinal chemistry origins of the new non-cytotoxic payloads.

Filanesib in combination with pomalidomide and dexamethasone in refractory MM patients: safety and efficacy, and association with alpha 1-acid glycoprotein (AAG) levels. Phase Ib/II Pomdefil clinical trial conducted by the Spanish MM group.

This phase I/II trial evaluated the combination of the kinesin spindle protein inhibitor filanesib with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma (RRMM) patients. Forty-seven RRMM patients with a median of three prior lines (2-8) and 94% refractory to lenalidomide were included: 14 in phase I and 33 in phase II. The recommended dose was 1·25 mg/m2 of filanesib on days 1, 2, 15, 16, with pomalidomide 4 mg on days 1-21 and dexamethasone 40 mg weekly. The defined threshold for success was achieved, with 18 out of 31 patients obtaining at least minor response (MR) in the phase II. In the global population, 51% of patients achieved at least partial response (PR) and 60% ≥MR, resulting in a median progression-free survival (mPFS) of seven months and overall survival (OS) of 19 months. The main toxicity was haematological. Importantly, patients with low serum levels of alpha 1-acid glycoprotein (AAG) at baseline (<800 mg/l) had a superior response (overall response rate of 62% vs. 17%; P = 0·04), which also translated into a longer mPFS (9 vs. 2 months; P = 0·014). In summary, filanesib with pomalidomide and dexamethasone is active in RRMM although with significant haematological toxicity. Most importantly, high levels of AAG can identify patients unlikely to respond to this strategy. Trial registration: clinicaltrials.gov identifier: NCT02384083.

Functional 1,3a,6a-triazapentalene scaffold: Design of fluorescent probes for kinesin spindle protein (KSP).

1,3a,6a-Triazapentalene is a compact fluorescent chromophore. In this study, triazapentalene was used to modify a series of biphenyl-type inhibitors of kinesin spindle protein (KSP) to develop fluorescent probes for the intracellular visualization of this protein. Microscopic studies demonstrated that these novel triazapentalene-labeled compounds exhibited inhibitory activity towards KSP in cultured cells and provided important information concerning the intracellular distribution.

Killer-specific secretory (Ksp37) gene expression in subjects with Down's syndrome.

Down syndrome is characterized by dysmorphic features, mental retardation and problems of immune deficiency. Chronic infection by Epstein-Barr virus is frequently present in subjects with Down syndrome. Ksp37 gene is commonly expressed by NK, CD8(+) T, γδ T and CD4(+) T cells; these data suggest that Ksp37 have cytotoxic properties. An increase of Ksp37 protein serum levels it has been showed during the acute phase of Epstein-Barr virus. In this study, we evaluated the expression of Ksp37 mRNA, in fibroblasts and leukocytes of DS subjects and in normal subjects with realtime reverse transcription-PCR. This analysis shows that in fibroblasts and leukocytes of Down syndrome subjects the KSP37 gene expression was increased compared with control subjects. The results of this study suggest that the expression of Ksp37 gene might be associated with increased susceptibility of individuals with Down syndrome to EBV infections and autoimmune problems.

Cathelicidin PR-39 peptide inhibits hypoxia/reperfusion-induced kidney cell apoptosis by suppression of the endoplasmic reticulum-stress pathway.

Ischemia/reperfusion injury (IRI) is a major cause of acute kidney damage, which often occurs in deceased donor kidney transplants. Cathelicidin PR-39 peptide possesses anti-inflammatory and wound repair effects through tissue angiogenesis and anti-apoptosis. This study assessed the role of PR-39 in anti-apoptosis in vitro using a lentiviral vector with a kidney specific promoter (KSP) to drive PR-39 expression. Our data revealed that PR-39 peptide was specifically over-expressed in kidney-derived HK-2 cells, but was scarcely detected in non-kidney tissue-derived cells. PR-39 over-expression had a protective role in the hypoxia/re-oxygenation (H/R) treated cells. The anti-apoptotic activity of PR-39 peptide was mediated by the inhibition of caspase-2, caspase-12 and caspase-3 activity in the endoplasmic reticulum (ER) stress-induced apoptotic pathway. It was also revealed that the anti-apoptotic effect of PR-39 peptide was mediated by an apoptosis-related protein, cellular inhibitor apoptosis protein-2 (c-IAP-2). Taken together, the current data demonstrate that PR-39 expression driven by KSP could prevent kidney damage (apoptosis) from IRI via the ER stress-induced apoptotic pathway.

New benzimidazoles and their antitumor effects with Aurora A kinase and KSP inhibitory activities.

A newly synthesized series of anticancer compounds comprising thiazolo[3,2-a]pyrimidine derivatives 6a-q bearing a benzimidazole moiety was produced via a one-pot reaction of N-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-2-cyanoacetamide 5 with 2-aminothiazole and an appropriate aromatic aldehyde. Compound 7 was obtained via the reaction of 4-(1H-benzo[d]imidazol-2yl)benzenamide 1 with carbon disulphide and methyl iodide in the presence of concentrated aqueous solution of NaOH, then treated with o-phenylenediamine to give N-(4-1H-benzo[d]imidazol-2-yl)phenyl)-1H-benzo[d]imidazol-2-amine 8. The structures of the newly synthesized compounds were confirmed by analytical and spectroscopic measurements (IR, MS, and (1) H NMR). The synthesized products were screened and studied for their in vitro antitumor activity against three human cancer cell lines (namely colorectal cancer cell line HCT116, human liver cancer cell line HepG2, and human ovarian cancer cell line A2780) and their Aurora A kinase and KSP inhibitory activities. All newly synthesized compounds revealed marked results comparable with the standard drug CK0106023. The compounds 6e and 6k of the thiazolopyrimidine derivatives were the most active compounds when tested against the three cell lines in comparison with the standard drug CK0106023, and showed potent dual KSP and Aurora A kinase inhibition.

Design of sports training information analysis system based on a multi-target visual model under sensor-scale spatial transformation.

In the contemporary realm of athletic training, integrating technology is a pivotal determinant for augmenting athlete performance and refining training outcomes. The amalgamation of multi-target visual modeling with sensor technology imparts an enriched stratum of sports training data. Subsequently, the sensor scale-space transformation accentuates the comprehensive apprehension of data across diverse scales and angles. Hence, within this manuscript, addressing the multi-target tracking intricacies during sports training and competition, we posit a framework that amalgamates the shortest path elucidated by the K shortest paths (KSP) methodology with the pose information emanating from the Alphapose network. This framework recognizes the athlete's shortest path through a convolutional neural network and KSP, followed by the amalgamation of these divergent data sources. The fusion unfolds by incorporating the athlete's pose information grounded in Alphapose, culminating in a comprehensive integration of the two data streams. Consequently, synthesizing alpha-derived athlete information precipitates the ultimate amalgamation of the two information streams. The accomplished fusion, premised on Alphapose, forms the bedrock for multi-target tracking, culminating in a feature-rich synthesis. Empirical results reveal that after integrating these information streams, the Multiple Object Tracking Accuracy (MOTA) index and Global Multiple Object Tracking Accuracy (GMOTA) index surpass those of the solitary information tracking methods, thereby furnishing a technical underpinning and a foundation for information fusion within prospective sports training analysis systems.

Coupling Kinesin Spindle Protein and Aurora B Inhibition with Apoptosis Induction Enhances Oral Cancer Cell Killing.

Many proteins regulating mitosis have emerged as targets for cancer therapy, including the kinesin spindle protein (KSP) and Aurora kinase B (AurB). KSP is crucial for proper spindle pole separation during mitosis, while AurB plays roles in chromosome segregation and cytokinesis. Agents targeting KSP and AurB selectively affect dividing cells and have shown significant activity in vitro. However, these drugs, despite advancing to clinical trials, often yield unsatisfactory outcomes as monotherapy, likely due to variable responses driven by cyclin B degradation and apoptosis signal accumulation networks. Accumulated data suggest that combining emerging antimitotics with various cytostatic drugs can enhance tumor-killing effects compared to monotherapy. Here, we investigated the impact of inhibiting anti-apoptotic signals with the BH3-mimetic Navitoclax in oral cancer cells treated with the selective KSP inhibitor, Ispinesib, or AurB inhibitor, Barasertib, aiming to potentiate cell death. The combination of BH3-mimetics with both KSP and AurB inhibitors synergistically induced substantial cell death, primarily through apoptosis. A mechanistic analysis underlying this synergistic activity, undertaken by live-cell imaging, is presented. Our data underscore the importance of combining BH3-mimetics with antimitotics in clinical trials to maximize their effectiveness.

The Application of Kinesin Inhibitors in Medical Issues.

Kinesins are a group of motor proteins in charge of several crucial functions in the cell. These proteins often bind to microtubules and perform their functions using the energy produced by ATP hydrolysis. One function of mitotic kinesin, a subclass of kinesin that is expressed during cell division at the mitotic phase, is to create the mitotic spindle. Uncontrolled cell growth is one trait of cancerous cells. Traditional anticancer medications still used in clinics include taxanes (paclitaxel) and vinca alkaloids (vincristine, vinblastine), which interfere with microtubule dynamics. However, because non-dividing cells like post-mitotic neurons contain microtubules, unwanted side effects like peripheral neuropathy are frequently found in patients taking these medications. More than ten members of the mitotic kinesin family play distinct or complementary roles during mitosis. The mitotic kinesin family's KSP, or Eg5, is regarded as its most dramatic target protein. The current work systematically reviews the use of kinesin inhibitors in the medical field. The challenges of KSP and the practical solutions are also examined, and the outcomes of the previous works are reported. The significant gaps and shortcomings of the related works are also highlighted, which can be an onset topic for future works.

Ksp1 is an autophagic receptor protein for the Snx4-assisted autophagy of Ssn2/Med13.

Ksp1 is a casein II-like kinase whose activity prevents aberrant macroautophagy/autophagy induction in nutrient-rich conditions in yeast. Here, we describe a kinase-independent role of Ksp1 as a novel autophagic receptor protein for Ssn2/Med13, a known cargo of Snx4-assisted autophagy of transcription factors. In this pathway, a subset of conserved transcriptional regulators, Ssn2/Med13, Rim15, and Msn2, are selectively targeted for vacuolar proteolysis following nitrogen starvation, assisted by the sorting nexin heterodimer Snx4-Atg20. Here we show that phagophores also engulf Ksp1 alongside its cargo for vacuolar proteolysis. Ksp1 directly associates with Atg8 following nitrogen starvation at the interface of an Atg8-family interacting motif (AIM)/LC3-interacting region (LIR) in Ksp1 and the LIR/AIM docking site (LDS) in Atg8. Mutating the LDS site prevents the autophagic degradation of Ksp1. However, deletion of the C terminal canonical AIM still permitted Ssn2/Med13 proteolysis, suggesting that additional non-canonical AIMs may mediate the Ksp1-Atg8 interaction. Ksp1 is recruited to the perivacuolar phagophore assembly site by Atg29, a member of the trimeric scaffold complex. This interaction is independent of Atg8 and Snx4, suggesting that Ksp1 is recruited early to phagophores, with Snx4 delivering Ssn2/Med13 thereafter. Finally, normal cell survival following prolonged nitrogen starvation requires Ksp1. Together, these studies define a kinase-independent role for Ksp1 as an autophagic receptor protein mediating Ssn2/Med13 degradation. They also suggest that phagophores built by the trimeric scaffold complex are capable of receptor-mediated autophagy. These results demonstrate the dual functionality of Ksp1, whose kinase activity prevents autophagy while it plays a scaffolding role supporting autophagic degradation.Abbreviations: 3-AT: 3-aminotriazole; 17C: Atg17-Atg31-Atg29 trimeric scaffold complex; AIM: Atg8-family interacting motif; ATG: autophagy related; CKM: CDK8 kinase module; Cvt: cytoplasm-to-vacuole targeting; IDR: intrinsically disordered region; LIR: LC3-interacting region; LDS: LIR/AIM docking site; MoRF: molecular recognition feature; NPC: nuclear pore complex; PAS: phagophore assembly site; PKA: protein kinase A; RBP: RNA-binding protein; UPS: ubiquitin-proteasome system. SAA-TF: Snx4-assisted autophagy of transcription factors; Y2H: yeast two-hybrid.

Liver as a target for oligonucleotide therapeutics.

Oligonucleotide-based therapeutics are an emerging class of drugs that hold the promise for silencing "un-druggable" targets,thus creating unique opportunities for innovative medicines. As opposed to gene therapy, oligonucleotides are considered to be more akin to small molecule therapeutics because they are small,completely synthetic in origin, do not integrate into the host genome,and have a defined duration of therapeutic activity after which effects recover to baseline. They offer a high degree of specificity at the genetic level, thereby reducing off-target effects.At the same time, they provide a strategy for targeting any gene in the genome, including transcripts that produce mutated proteins.Oligonucleotide-based therapeutics include short interfering RNA (siRNA), that degrade target mRNA through RISC mediated RNAi; anti-miRs, that target miRNAs; miRNA mimics, that regulate target mRNA; antisense oligonucleotides, that may be working through RNAseH mediated mRNA decay; mRNA upregulation,by targeting long non-coding RNAs; and oligonucleotides induced alternative splicing [1]. All these approaches require some minimal degree of homology at the nucleic acid sequence level for them to be functional. The different mechanisms of action and their relevant activity are outlined in Fig. 1. Besides homology,RNA secondary structure has also been exploited in the case of ribozymes and aptamers, which act by binding to nucleic acids or proteins, respectively. While there have been many reports of gene knockdown and gene modulation in cell lines and mice with all these methods, very few have advanced to clinical stages.The main obstacle to date has been the safe and effective intracellular delivery of these compounds in higher species, including humans. Indeed, their action requires direct interaction with DNA/RNA within the target cell so even when one solves the issues of tissue and cellular access, intracellular/intranuclear location represents yet another barrier to overcome. To date,hepatic delivery of oligonucleotides has been the area with greatest progress, and thus we have focused on liver-targeted therapeutics that have shown promise at the preclinical and/or clinical level.The liver is the largest internal organ in the body, playing a central role in metabolism, detoxification, synthesis, and secretion of major plasma proteins (carrier proteins, coagulation factors,complement components, hormones, and apolipoproteins),and iron homeostasis. It is therefore not surprising that a large number of disease targets reside in the liver where they are susceptible to modulation by oligonucleotide therapies.

Alpha-induced production and robust radiochemical separation of 43Sc as an emerging radiometal for formulation of PET radiopharmaceuticals.

Scandium-43 is an emerging PET radiometal that was produced by α-particle bombardment on natural CaCO3 target via natCa (α,p) 43Sc and natCa (α,n) 43Ti→43Sc reactions using K-130 cyclotron at VECC. A robust radiochemical procedure based on selective precipitation of 43Sc as Sc(OH)3 was developed for separation of the radioisotope from the irradiated target. The overall yield of the separation process was >85% and it was obtained in a form suitable for preparation of target specific radiopharmaceuticals for PET imaging of cancer.

Role of KSP Inhibitors as Anti-cancer Therapeutics: An Update.

Regardless of the growing discovery of anticancer treatments targeting cancer-specific pathways, cytotoxic therapy still maintained its abundant clinical significance because tumours harbor a greater population of actively dividing cells than normal tissues. Conventional anti-mitotic agents or microtubule poisons acting on the major mitotic spindle protein tubulin have been effectively used in clinical settings for cancer chemotherapy over the last three decades. However, the use of these drugs is associated with limited clinical utility due to serious side effects such as debilitating and dose-limiting peripheral neuropathy, myelosuppression, drug resistance, and allergic reactions. Therefore, research initiatives have been undertaken to develop novel microtubule motor proteins inhibitors that can potentially circumvent the limitations associated with conventional microtubule poisons. Kinesin spindle proteins (KSP) belonging to the kinesin-5 family play a crucial role during mitosis and unregulated cell proliferation. Evidence from preclinical studies and different phases of clinical trials have presented kinesin spindle protein as a promising target for cancer therapeutics. Kinesin spindle protein inhibitors causing mitosis disruption without interfering with microtubule dynamics in non-dividing cells offer a potential therapeutic alternative for the management of several major cancer types and are devoid of side effects associated with classical anti-mitotic drugs. This review summarizes recent data highlighting progress in the discovery of targeted KSP inhibitors and presents the development of scaffolds, structure-activity relationships, and outcomes of biological and enzyme inhibition studies. We reviewed the recent literature reports published over the last decade, using various electronic database searches such as PubMed, Embase, Medline, Web of Science, and Google Scholar. Clinical trial data till 2021 was retrieved from ClinicalTrial.gov. Major chemical classes developed as selective KSP inhibitors include dihydropyrimidines, ß-carbolines, carbazoles, benzimidazoles, fused aryl derivatives, pyrimidines, fused pyrimidines, quinazolines, quinolones, thiadiazolines, spiropyran, and azobenzenes. Drugs such as filanesib, litronesib, ispinesib have entered clinical trials; the most advanced phase explored is Phase II. KSP inhibitors have exhibited promising results; however, continued exploration is greatly required to establish the clinical potential of KSP inhibitors.

Antibody-drug conjugates harboring a kinesin spindle protein inhibitor with immunostimulatory properties.

Antibody-drug conjugates (ADCs) are used to target cancer cells by means of antibodies directed to tumor-associated antigens, causing the incorporation of a cytotoxic payload into target cells. Here, we characterized the mode of action of ADC costing of a TWEAKR-specific monoclonal antibody conjugated to a small molecule kinesin spindle protein (KSP) inhibitor (KSPi). These TWEAKR-KSPi-ADCs showed strong efficacy in a TWEAKR expressing CT26 colon cancer model in mice. TWEAKR-KSPi-ADCs controlled the growth of CT26 colon cancers in immunodeficient as well as in immunocompetent mice. However, when treated with suboptimal doses, TWEAKR-KSPi-ADCs were still active in immunocompetent but not in immunodeficient mice, indicating that TWEAKR-KSPi-ADCs act - in addition to the cytotoxic mode of action - through an immunological mechanism. Indeed, in vitro experiments performed with a cell-permeable small molecule KSPi closely related to the active payload released from the TWEAKR-KSPi-ADCs revealed that KSPi was capable of stimulating several hallmarks of immunogenic cell death (ICD) on three different human cancer cell lines: cellular release of adenosine triphosphate (ATP) and high mobility group B1 protein (HMGB1), exposure of calreticulin on the cell surface as well as a transcriptional type-I interferon response. Further, in vivo experiments confirmed that treatment with TWEAKR-KSPi-ADCs activated immune responses via enhancing the infiltration of CD4+ and CD8+ T lymphocytes in tumors and the local production of interferon-γ, interleukin-2, and tumor necrosis factor-α. In conclusion, the antineoplastic effects of TWEAKR-KSPi-ADCs can partly be attributed to its ICD-stimulatory properties.

Kinesin spindle protein inhibitors in cancer: from high throughput screening to novel therapeutic strategies.

Bringing to a halt the cell cycle in mitosis and interfering with its normal progression is one of the most successful anti-cancer strategies used nowadays. Classically, several kinds of anti-cancer drugs like taxanes and vinca alkaloids directly inhibit microtubules during cell division. These drugs exhibit serious side effects, most importantly, severe peripheral neuropathies. Alternatively, KSP inhibitors are grasping a lot of research attention as less toxic mitotic inhibitors. In this review, we track the medicinal chemistry developmental stages of KSP inhibitors. Moreover, we address the challenges that are faced during the development of KSP inhibitor therapy for cancer and future insights for the latest advances in research that are directed to find active KSP inhibitor drugs.

The role of endoscopic management and adjuvant topical therapy for upper tract urothelial cancer.

Upper tract urothelial carcinoma (UTUC) has traditionally been managed with radical nephroureterectomy, and while this approach remains the gold standard for high-risk disease, endoscopic, kidney-sparing management has increasingly been adopted for low-risk disease as it preserves kidney function without compromising oncologic outcomes. Ureteroscopy and percutaneous renal access not only provide diagnoses by tumor visualization and biopsy, but also enable treatment with electrocautery or laser ablation. Several modalities exist for laser ablative treatments including thulium:YAG, neodymium:YAG, holmium:YAG, and combinations of the preceding. Furthermore, due to high recurrence rates after endoscopic management, adjuvant intracavitary instillation of various agents such as mitomycin C and bacillus Calmette-Guerin have been used given benefits seen in non-muscle invasive urothelial bladder cancer. Other formulations also being studied include gemcitabine, anthracyclines, and immunotherapies. More recently, Jelmyto, a mitomycin reverse thermal gel, has been developed to allow for adequate drug delivery time and potency since urine flow could otherwise dilute and washout topical therapy. In this article, the authors review techniques, indications, best practices, and areas of current investigation in endoscopic management and adjuvant topical therapy for UTUC.

The removal of heavy metal cations by sulfidated nanoscale zero-valent iron (S-nZVI): The reaction mechanisms and the role of sulfur.

In this study, the reaction between sulfidated nanoscale zero-valent iron (S-nZVI) and heavy metal cations as well as the role of sulfur were investigated. The results showed the corrosion products of S-nZVI were lepidocrocite (γ-FeOOH) or/and magnetite (Fe3O4), depending on heavy metal species. While the removal of Hg(II), Ag(I), Cu(II), and Pb(II) by S-nZVI was rapid and could achieve over 99% within 5 mins, the removal of Ni(II) and Zn(II) was low in efficiency and unstable. Sulfur was existed as iron sulfides at fresh S-nZVI, but was displaced by the heavy metals and formed the related sulfide compound, or oxidized to S0 and SO42-. The removal mechanisms are strongly dependent on the solubility product constant (Ksp) of metal sulfides. For Hg(II) and Ag(I), with Ksp of corresponding metal sulfides much lower than that of iron sulfide, the removal mechanism is the displacement reaction. For Cu(II) and Pb(II), with Ksp of corresponding metal sulfides moderately lower than that of iron sulfide, the removal mechanisms are the displacement reaction and complexation with surface groups of S-nZVI. For Zn(II) and Ni(II), whose Ksp of corresponding metal sulfides slightly lower than that of iron sulfide, are mainly removed by complexation with surface groups of S-nZVI.

Filanesib for the treatment of multiple myeloma.

Introduction: Kinesin spindle protein (KSP) is indispensable for the proper separation of spindle poles during mitosis. Importantly, this protein is expressed only in cells undergoing cell division and hence represents an appealing target for the treatment of cancer. Many KSP inhibitors have demonstrated a strong antitumoral effect in vitro, however, they have exhibited only limited activity in clinical trials. By contrast, the KSP inhibitor filanesib has demonstrated clinical efficacy in patients with multiple myeloma (MM).Areas covered: This article provides a comprehensive overview about the progress to date in the preclinical and clinical development of filanesib for the treatment of cancer, and particularly, MM.Expert opinion: Responses observed with filanesib alone or in combination with dexamethasone were encouraging in MM. However, the subsequent appearance of highly effective novel agents such as monoclonal antibodies, has hindered the development of agents such as filanesib that exhibit a more limited activity. Nevertheless, filanesib has shown interesting results for some patients when combined with carfilzomib and pomalidomide. Most importantly, the availability of a biomarker of response such as alpha 1-acid glycoprotein (AAG), could be key to the identification of patients that could benefit most from these combinations.

KSP siRNA/paclitaxel-loaded PEGylated cationic liposomes for overcoming resistance to KSP inhibitors: Synergistic antitumor effects in drug-resistant ovarian cancer.

Despite the promising anticancer effects of kinesin spindle protein (KSP) inhibition, functional plasticity of kinesins induced resistance against KSP inhibitors in a variety of cancers, leading to clinical failure. Additionally, paclitaxel is a widely used anticancer agent, but drug resistance has limited its use in the recurrent cancers. To overcome resistance against KSP inhibitors, we paired KSP inhibition with microtubule stabilization using KSP siRNA and paclitaxel. To enable temporal co-localization of both drugs in tumor cells in vivo, we exploited PEGylated cationic liposomes carrying both simultaneously. Drug synergism study shows that resistance against KSP inhibition can be suppressed by the action of microtubule-stabilizing paclitaxel, because microtubule stabilization prevents a different kinesin Kif15 from replacing all essential functions of KSP when KSP is inhibited. Our combination therapy showed more effective antiproliferative activity in vitro and in vivo than either paclitaxel or KSP siRNA alone. Ultimately, we could observe significantly improved therapeutic effects in the drug-resistant in vivo models, including cell line and patient-derived xenografts. Taken together, our combination therapy provides a potential anticancer strategy to overcome resistance against KSP inhibitors. Particularly, this strategy also provides an efficient approach to improve the therapeutic effects of paclitaxel in the drug-resistant cancers.