Kinesin Spindle Protein Inhibitor Research Articles

Phase 1 Study of the Novel Kinesin Spindle Protein Inhibitor Filanesib + Carfilzomib in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM)

Phase 1 Study of the Novel Kinesin Spindle Protein Inhibitor Filanesib + Carfilzomib in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM)

Phase 2 Study of Carfilzomib (CFZ) with or without Filanesib (FIL) in Patients with Advanced Multiple Myeloma (MM)

Background: FIL (ARRY-520), a specific kinesin spindle protein (KSP) inhibitor, represents a novel class of agent under investigation for the treatment of patients (pts) with MM. Prognosis of pts refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) is poor. These pts have a median survival of 9 months underscoring the importance of novel therapeutic strategies incorporating new mechanisms of action. FIL has shown interesting preliminary activity as a single agent as well as in Phase 1 studies in combination with bortezomib (BTZ) and with CFZ, all with a manageable safety profile. Methods: This trial is an ongoing, randomized, multicenter, open-label Phase 2 study for pts with relapsed and refractory MM who received at least 2 prior regimens, including BTZ and an IMiD, and with disease refractory to the last regimen as per IMWG criteria. No prior treatment with CFZ is allowed. Approximately 75 pts will be randomized 2:1 to receive CFZ (20/27 mg/m2 intravenous [IV] on Days 1, 2, 8, 9, 15 and 16) plus FIL (1.25 mg/m2 IV on Days 1, 2, 15 and 16) or single-agent CFZ, at the same dose as in the combination, in a 28-day cycle. Prophylactic filgrastim is administered in the CFZ + FIL arm. The primary endpoint is progression-free survival (PFS). Patients with progressive disease (PD) on CFZ are allowed cross-over to the CFZ + FIL arm if they continue to meet eligibility criteria. Results: As of 15 June 2015, 72 pts have been randomized (23 CFZ, 49 CFZ + FIL) with a median age of 65 years. Pts who could have potentially received ≥ 2 cycles of treatment (20 CFZ, 30 CFZ + FIL) were evaluable for efficacy. These pts were heavily pretreated with a median of 4 and 5 prior regimens in the CFZ and CFZ + FIL arm, respectively. A total of 25% and 30 % of pts, respectively, received prior pomalidomide. The objective response rate (ORR) was 10% in the CFZ arm and 30% in the CFZ + FIL arm. In the CFZ arm, 2 pts achieved a partial response (PR) and 2 pts (10%) achieved an MR. In the CFZ + FIL arm, 3 pts achieved a very good partial response and 6 pts achieved a PR, with 2 additional pts (7%) achieving an MR. In the population of pts who were refractory to both prior BTZ and prior IMiDs, the ORR was 14% and 35%, respectively. Grade 3-4 hematological laboratory abnormalities (≥ 5% of pts) were leukopenia (9% CFZ vs. 21% CFZ + FIL), neutropenia (14% vs. 24%), thrombocytopenia (14% vs. 24%), and anemia (9% vs. 26%). Neutropenia and thrombocytopenia were reversible. No adverse events (AEs) of febrile neutropenia were reported. The only Grade 3-4 non-hematological AE occurring in ≥ 5% of pts was dyspnea (5% vs.11%). The most common reason for treatment discontinuation was confirmed PD (39% vs. 28%) or Investigator discretion in case of unconfirmed PD or clinical PD (17% vs. 12%). Conclusions: The combination of FIL and CFZ was well-tolerated and noticeably increased the ORR compared to CFZ alone in heavily pretreated pts with advanced MM. The preliminary efficacy in pts who are double refractory to IMiDs and BTZ who were randomized to CFZ + FIL appears higher than in pts treated with CFZ alone (in the CFZ arm of this trial and in previously published reports involving such pts). Updated safety and efficacy data, including PFS, will be presented at the meeting. Disclosures Zonder:Seattle Genetics: Membership on an entity9s Board of Directors or advisory committees; Prothena: Membership on an entity9s Board of Directors or advisory committees; BMS: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees, Other: research support. Off Label Use: carfilzomib; treatment of myeloma, but not in combination with filanesib. Usmani:Celgene Corporation: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Research Funding. Berdeja:Onyx: Research Funding; Array: Research Funding; Takeda: Research Funding; Acetylon: Research Funding; Janssen: Research Funding; BMS: Research Funding; MEI: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Curis: Research Funding. Anderson:Onyx: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Hari:BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. Singhal:Celgene: Speakers Bureau. Valent:Takeda/Millennium: Speakers Bureau; Celgene: Speakers Bureau. Faber:Celgene: Consultancy. Schiller:Sunesis: Honoraria, Research Funding. Schreiber:Array BioPharma: Employment. Oliver:Array BioPharma: Employment. Rush:Array BioPharma: Employment. Tunquist:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Employment. Raje:Eli Lilly: Research Funding; Millenium: Consultancy; Takeda: Consultancy; Onyx: Consultancy; Acetylon: Research Funding; BMS: Consultancy; AstraZeneca: Research Funding; Novartis: Consultancy; Amgen: Consultancy; Celgene Corporation: Consultancy; Acetylon: Research Funding.

How to incorporate the Newest Agents Combo vs Sequence - in Favor of Sequence

Treatment paradigms for multiple myeloma have changed significantly in the past decade due to introduction of new drugs. Alkylators, corticosteroids and anthracyclines remained the cornerstone of myeloma therapy until the introduction of proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs). Over the past decade there has been an explosion of new drugs that are being evaluated in myeloma and other plasma cell disorders. Among these, histone deacetylase inhibitor class has been the latest addition to the armamentarium and monoclonal antibodies are likely to enter the arena in the near future. Along with this, several other classes of drugs are undergoing later stage trials including specific HDAC inhibitors, kinesin spindle protein inhibitors, signal transduction pathway inhibitors, and cyclin dependent kinase inhibitors to name a few. Along with these blessings comes the challenge of positioning these drugs for treatment of myeloma in the most effective manner. A major focus of ongoing debates in the field is the optimal sequencing of the different drugs, particularly multidrug combinations versus single agent with or with out dexamethasone. It is clear that combinations of new drugs can lead to deeper responses in a higher proportion of patients compared with those containing only one of the newer drugs. It is also clear from phase 3 trials that these deeper responses lead to longer progression free survival. However, given that the current treatment approaches have not led to a cure for this disease and we have to eventually face disease relapse, would it be better to use one class of drug at a time in order to maximize their use. The case for combinations and deeper responses would have been clear had these trials demonstrated an improved overall survival when combinations are compared to new drugs used one at a time, suggesting a fundamental alteration in the natural history of the disease. However, this data is lacking at this time. However, it is likely that eventual cure of the disease will come from judicious combination of drugs, but these should be explored in th context of clinical trials.

Structure-Guided Design of Novel l-Cysteine Derivatives as Potent KSP Inhibitors.

Kinesin spindle protein (KSP), known as Hs Eg5, a member of the kinesin-5 family, plays an important role in the formation and maintenance of the bipolar spindle. We previously reported S-trityl-l-cysteine derivatives as selective KSP inhibitors. Here, we report further optimizations using docking modeling in the L5 allosteric binding site, which led to the discovery of several high affinity derivatives with two fused phenyl rings in the trityl group giving low nanomolar range KSP ATPase inhibition. The representative derivatives potently inhibited cell growth of HCT116 cells in correlation with KSP inhibitory activities and significantly suppressed tumor growth in the xenograft model in vivo.

Potential new chemotherapy strategy for human ovarian carcinoma with a novel KSP inhibitor

Among synthetic kinesin spindle protein (KSP) inhibitor compounds, KPYB10602, a six-member lactam-fused carbazole derivative was the most potent in vitro against cell growth of human ovarian cancer, A2780. KPYB10602 caused dose-dependent suppression of tumor growth in vivo. Mitotic arrest due to KPYB10602 was confirmed in vitro, and was characterized by inhibition of securin degradation. Apoptosis after mitotic arrest was associated with an increase in the ratio of pro-apoptotic Bax to anti-apoptotic Bcl-2. Increase of reactive oxygen species (ROS) and caspase pathway were also involved. Furthermore, KPYB10602 caused little neurotoxicity in vivo. Therefore, KPYB10602 could be a promising candidate as an anti-tumor agent with reduced adverse events for treating human ovarian cancer.

The novel kinesin spindle protein (KSP) inhibitor SB-743921 exhibits marked activity in in vivo and in vitro models of aggressive large B-cell lymphoma

The kinesin spindle protein (KSP) is a mitotic protein essential for cell cycle control and motility. SB-743921 (hereafter SB-921) is an inhibitor that selectively targets the ATP-binding domain of the KSP. The preclinical activity of SB-921 was evaluated in models of diffuse large B-cell lymphoma (DLBCL). The cytotoxicity of SB-921 was evaluated in a series of germinal center (GC-DLBCL) and post-germinal center (ABC-DLBCL) DLBCL cell lines and a murine lymphoma xenograft model. GC-DLBCL lines generally demonstrated greater sensitivity to SB-921. IC50 values ranged between 1 nM and 900 nM for GC-DLBCL compared to 1 nM to 10 μM for ABC lines. SB-921 demonstrated marked activity in a xenograft model of Ly-1 (GC-DLBCL). While SB-921 was relatively more active in GC derived cell lines, ABC-derived lines still underwent apoptosis at higher concentrations. These results demonstrate that SB-921 inhibits proliferation and induces apoptosis in both GC-DLBCL and ABC-DLBCL.

Discovery of novel spiro 1,3,4-thiadiazolines as potent, orally bioavailable and brain penetrant KSP inhibitors

Kinesin spindle protein (KSP) is a mitotic kinesin that is expressed only in proliferating cells and plays a key role in spindle pole separation, formation of a bipolar mitotic spindle, as well as centrosome separation and maturation. Inhibition of KSP has the potential to provide anti-tumor activity while avoiding peripheral neuropathy associated with some microtubule-targeted drugs. Based on MK-0731 and related heterocyclic compounds targeting the KSP monastrol binding site, structurally constrained spiro-cyclic KSP inhibitors were designed. In particular, rapid evaluation and optimization of the novel spiro 1,3,4-thiadiazolines resulted in a series of potent KSP inhibitors demonstrating mechanism based activities in cells, including induction of the mitotic marker phospho-histone H3 and induction of monaster spindle formation. Further optimization of the pharmacokinetic (PK) properties afforded MK-8267 as a potent, orally bioavailable and brain penetrant KSP inhibitor which showed anti-tumor activity in preclinical xenograft models.

Targeting Cancer Cells During Mitosis Using Novel S-Trityl-LCysteine(STLC) Analogs

The design of synthetic small molecules that target cytoskeleton microtubule is important for the investigation of the mechanism of cell division and for the development of novel anti-tumor agents. Molecules targeting microtubule stability such as Taxanes and Vinca alkaloids are among the most successful anticancer agents. However, such molecules cause undesired side effects, including neurotoxicity, and are subject to acquired drug resistance. In 1999, researchers discovered a completely new target for anti-mitotic activity is the microtubuleassociated kinesin Eg5 (kinesin spindle protein, KSP). Eg5 is a member of the kinesin-5 family and plays an important role in the early stages of mitosis. Specifically, kinesin Eg5 plays an important role in bipolar spindle formation. Inhibition of this motor protein leads to the formation of monopolar spindles, mitotic arrest, followed by cell apoptosis. Molecules targeting KSP selectively act only on the cells undergoing cell division, making them mitosis-specific drugs. S-trityl-L-cysteine (STLC) is a potent allosteric inhibitor of kinesin spindle protein (KSP); however, this compound has limited potential use for cancer treatment due to its amphiphilic and poor drug-like characteristics.

Histone H3 Phosphorylation in Human Skin Histoculture as a Tool to Evaluate Patient's Response to Antiproliferative Drugs.

Evaluation of patient’s response to chemotherapeutic drugs is often difficult and time consuming. Skin punch biopsies are easily accessible material that can be used for the evaluation of surrogate biomarkers of a patient’s response to a drug. In this study, we hypothesized that assessment of phosphorylated histone H3 in human skin punch biopsies could be used as a pharmacodynamics biomarker of patient’s response to the kinesin spindle protein inhibitor SCH2047069. To test this hypothesis, we used a human skin histoculture technique that allows culturing intact human skin in the presence of the drug. Human melanoma and skin histocultures were treated with SCH2047069, and the effect of the drug was assessed by increasing histone H3 phosphorylation using immunohistochemistry. Our results demonstrate that SCH2047069 has a significant effect on cell proliferation in human melanoma and skin histoculture and justify using human skin punch biopsies for evaluation of the pharmacodynamic changes induced by SCH2047069.ACRONYMSHistone subunit H3 (H3), Kinesin spindle protein (KSP), 5-ethynyl-2′-deoxyuridine (EDU), Dimethyl sulfoxide (DMSO), Formalin-fixed paraffin embedded (FFPE).

Multiple myeloma: a model for scientific and clinical progress.

Multiple myeloma (MM) is a unique cancer paradigm for investigating the mechanisms involved in the transition from a premalignant condition (monoclonal gammopathy of undetermined significance) into a malignant disease (MM). In the pathogenesis of myeloma, the dialogue between plasma cells and their microenvironment is as important as the genotypic characteristics of the tumor clone. MM is genetically highly complex, with almost all patients displaying cytogenetic abnormalities and frequent intraclonal heterogeneity that play a critical role in the outcome of the disease. In fact, it is likely that myeloma will soon no longer be considered as a single entity. This, along with the availability of an unexpected number of new treatment possibilities, has reinforced the need for better tools for prognosis and for monitoring treatment efficacy through minimal residual disease techniques. The outcome of MM patients has significantly improved in the last 2 decades, first through the introduction of high-dose therapy followed by autologous stem cell transplantation and, more recently, due to the use of proteasome inhibitors (bortezomib and carfilzomib) and immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide). Moreover, the need to reexamine the diagnostic criteria of early MM and the possibility of early intervention opens up new therapeutic avenues. New drugs are also emerging, including second- and third-generation proteasome inhibitors and immunomodulators, monoclonal antibodies, histone deacetylase inhibitors, and kinesin spindle protein inhibitors, among others. Our goal is to find a balance among efficacy, toxicity, and cost, with the ultimate aim of achieving a cure for this disease.

Palladium-catalyzed enantioselective decarboxylative cycloaddition of vinylethylene carbonates with isocyanates.

An efficient method for the enantioselective construction of β-substituted β-vinylglycinol derivatives through palladium-catalyzed decarboxylative cycloaddition of vinylethylene carbonates with isocyanates was developed. By using a palladium complex generated in situ from [Pd2 (dba)3]⋅CHCl3 (dba=dibenzylideneacetone) and (S)-Segphos as a catalyst under mild reaction conditions, the process provided 4-substituted-4-vinyloxazolidin-2-ones in high yields with a high level of enantioselectivity. The stereochemical outcome of the reaction was explained by DFT calculations and the synthetic utility of the process was demonstrated by the gram-scale transformation and formal synthesis of MK-0731 as a kinesin spindle protein inhibitor.

Kinesin spindle protein inhibitor SB743921 induces mitotic arrest and apoptosis and overcomes imatinib resistance of chronic myeloid leukemia cells

Inhibition of the cell mitotic pathway may provide a novel means for therapeutic intervention in chronic myeloid leukemia (CML). Kinesin spindle protein (KSP), a microtubule-associated motor protein which is essential for cell cycle progression, is overexpressed in bcr–abl+ CML cells. Retrovirus mediated bcr–abl transduction increases KSP expression in cord blood CD34 + cells. SB743921 is a selective KSP inhibitor which is being investigated in ongoing clinical trials for treatment of myeloma, leukemia and solid tumors. Treatment of CML cells with SB743921 resulted in reduced proliferation and colony forming cell (CFC) formation ability. SB743921 also actively blocked cell cycle progression, leading to apoptosis in both primary CML cells and cell lines. KSP inhibition sensitized CML cells to imatinib-induced apoptosis. Importantly, SB743921 inhibited the proliferation of various CML cells including T315I mutation-harboring cells. Furthermore, we demonstrated that SB743921 treatment suppressed ERK and AKT activity in CML cells. These data indicate that SB743921 may become a novel treatment agent for patients with CML.

Structure-based design of new KSP-Eg5 inhibitors assisted by a targeted multicomponent reaction.

An integrated multidisciplinary approach that combined structure-based drug design, multicomponent reaction synthetic approaches and functional characterization in enzymatic and cell assays led to the discovery of new kinesin spindle protein (KSP) inhibitors with antiproliferative activity. A focused library of new benzimidazoles obtained by a Ugi+Boc removal/cyclization reaction sequence generated low-micromolar-range KSP inhibitors as promising anticancer prototypes. The design and functional studies of the new chemotypes were assessed by computational modeling and molecular biology techniques. The most active compounds-20 (IC50 =1.49 μM, EC50 =3.63 μM) and 22 (IC50 =1.37 μM, EC50 =6.90 μM)-were synthesized with high efficiency by taking advantage of the multicomponent reactions.

First-in-human study of 4SC-205 (AEGIS), a novel oral inhibitor of Eg5 kinesin spindle protein.

2564 Background: 4SC-205 is a potent small molecule inhibitor of the kinesin spindle protein Eg5 with broad anti-tumour activity in vitro and in vivo. Currently, 4SC-205 is the only oral available ...

Optimization of diaryl amine derivatives as kinesin spindle protein inhibitors

Structure–activity relationship studies of diaryl amine-type KSP inhibitors were carried out. Diaryl amine derivatives with a pyridine ring or urea group were less active when compared with the parent carboline and carbazole derivatives. Optimization studies of a lactam-fused diphenylamine-type KSP inhibitor revealed that the aniline NH group and 3-CF3 phenyl group were indispensable for potent KSP inhibition. Modification with a seven-membered lactam-fused phenyl group and a 4-(trifluoromethyl)pyridin-2-yl group improved aqueous solubility while maintaining potent KSP inhibitory activity. From these studies, we identified novel diaryl amine-type KSP inhibitors with a favorable balance of potency and solubility.

Kinesin spindle protein inhibitors with diaryl amine scaffolds: crystal packing analysis for improved aqueous solubility.

Diaryl amine derivatives have been designed and synthesized as novel kinesin spindle protein (KSP) inhibitors based on planar carbazole-type KSP inhibitors with poor aqueous solubility. The new generation of inhibitors was found to show comparable inhibitory activity and high selectivity for KSP, and this was accompanied with improved solubility. Kinetic analysis and molecular modeling studies suggested that these inhibitors work in an ATP-competitive manner via binding to the secondary allosteric site formed by α4 and α6 helices of KSP. Comparative structural investigations on a series of compounds revealed that the higher solubility of diaryl amine-type inhibitors was attributed to fewer van der Waals interactions in the crystal packing and the hydrogen-bond acceptor nitrogen of the aniline moiety for favorable solvation.

Developments of Kinesin Spindle Protein Inhibitors as Antitumor Agents Based on the Five-membered Heterocycle Scaffolds

Kinesin spindle protein (KSP) plays an essential role in centrosome separation and formation of the bipolar mitotic spindle. Its exclusive involvement in the mitotic spindle of proliferating cells presents an opportunity for developing new anticancer agents with reduced side effects relative to antimitotics that target tubulin. Small molecule KSP inhibitors have demonstrated their potential as novel antimitotic agents. Several KSP inhibitors have progressed into clinical trials and many others are in preclinical developments. Recently, KSP inhibitors of wide structural diversity have appeared in literatures. This review will summarize the developments of KSP inhibitors based on the five-membered heterocycle scaffolds in recent 10 years. These small molecule KSP inhibitors were classified as dihydropyrazoles, dihydropyrroles, thiophenes, dihydrothiadiazoles, thiazoles and fused pyrroles, their structure-activity relationships were discussed.

ChemInform Abstract: Kinesin Spindle Protein (KSP) Inhibitors in Combination with Chemotherapeutic Agents for Cancer Therapy

AbstractReview: 134 refs.

Heterogeneity of outcome with single-agent carfilzomib: all relapsed/refractory myelomas are not created equal

Since the year 2000, there has been a continued improvement in survival outcomes for multiple myeloma (MM) patients,1 attributable to the clinical development and inclusion of novel agents in upfront therapy, and improvement in high-dose therapy administration.2 There has been a growing body of literature furthering the biological understanding of the disease. There is a clear recognition of both inter-patient and intra-patient genomic heterogeneity in multiple myeloma,3 although the academic community is still trying to comprehend specific phenotypic presentations such as primary plasma cell leukemia4 and extramedullary disease.5 Even with effective upfront therapeutic strategies, which seemingly help a greater proportion of MM patients achieve a ‘complete’ remission by biochemical and pathology criteria, relapses do occur sooner or later that require subsequent lines of therapy. There is a growing list of classes of novel agents that are disease-relevant and showing promise in early clinical investigations in the relapsed/refractory MM (RRMM) setting. These classes include histone deacytelase inhibitors, heat-shock protein inhibitors, kinesin spindle protein inhibitors, immune-therapeutics and ubiquitin-proteasome pathway targeting agents.6 We have witnessed the Food and Drug Administration approval of two novel agents in the past 12 months, namely carfilzomib and pomalidomide, in the RRMM setting. It is highly likely that several novel agents will acquire Food and Drug Administration approval for RRMM over the next 5 years. The challenges in this setting would then be to determine which class of drugs may be more suitable for an individual patient, whether it would be better to sequence or combine different drug classes, and whether or not it would be possible to achieve ‘functional cure’ by making RRMM a chronic disease for most patients.

New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma Working Group (IMWG).

Treatment in medical oncology is gradually shifting from the use of nonspecific chemotherapeutic agents toward an era of novel targeted therapy in which drugs and their combinations target specific aspects of the biology of tumor cells. Multiple myeloma (MM) has become one of the best examples in this regard, reflected in the identification of new pathogenic mechanisms, together with the development of novel drugs that are being explored from the preclinical setting to the early phases of clinical development. We review the biological rationale for the use of the most important new agents for treating MM and summarize their clinical activity in an increasingly busy field. First, we discuss data from already approved and active agents (including second- and third-generation proteasome inhibitors (PIs), immunomodulatory agents and alkylators). Next, we focus on agents with novel mechanisms of action, such as monoclonal antibodies (MoAbs), cell cycle-specific drugs, deacetylase inhibitors, agents acting on the unfolded protein response, signaling transduction pathway inhibitors and kinase inhibitors. Among this plethora of new agents or mechanisms, some are specially promising: anti-CD38 MoAb, such as daratumumab, are the first antibodies with clinical activity as single agents in MM. Moreover, the kinesin spindle protein inhibitor Arry-520 is effective in monotherapy as well as in combination with dexamethasone in heavily pretreated patients. Immunotherapy against MM is also being explored, and probably the most attractive example of this approach is the combination of the anti-CS1 MoAb elotuzumab with lenalidomide and dexamethasone, which has produced exciting results in the relapsed/refractory setting.