Ixazomib

Bacterial caseinolytic protease P subunit (ClpP) is important and vital for cell survival and infectivity. Recent publications describe and discuss the complex structure-function relationship of ClpP and its processive activity mediated by 14 catalytic sites. Even so, there are several aspects yet to be further elucidated, such as the paradoxical allosteric modulation of ClpP by peptidomimetic boronates. These compounds bind to all catalytic sites, and in specific conditions, they stimulate a dysregulated degradation of peptides and globular proteins, instead of inhibiting the enzymatic activity, as expected for serine proteases in general...

This phase II study evaluated time-limited (24 cycles) treatment with ibrutinib and ixazomib in newly diagnosed (NDWM; n = 9) and relapsed/refractory (RRWM; n = 12) Waldenström macroglobulinaemia (WM). The overall response rate (ORR) was 76.2% (n = 16) in 21 evaluable patients with no patient achieving a complete response (CR). The median duration of treatment was 15.6 months, and after a median follow-up time of 25.7 months, the median progression-free survival (PFS) was 22...

The standard treatment for canine lymphoma is the CHOP chemotherapy regimen. Proteasome inhibitors have been employed with CHOP for the treatment of human haematological malignancies but remain to be fully explored in canine lymphoma. We identified an association between poor response to CHOP chemotherapy and high mRNA expression levels of proteasomal subunits in a cohort of 15 canine lymphoma patients, and sought to determine the effect of proteasome inhibitors on the viability of a canine B-cell lymphoma cell line (CLBL-1)...

MYC-aberrant non-Hodgkin lymphoma (NHL) is associated with poor outcomes with conventional chemotherapy. Ixazomib is an orally bioavailable proteasome inhibitor that targets drivers of MYC expression and has demonstrated preclinical activity in aggressive MYC-aberrant NHL. We conducted a phase I/II study evaluating the safety and efficacy of induction DA-EPOCH-R and ixazomib followed by ixazomib maintenance in aggressive MYC-aberrant NHL. For induction, patients received 6 cycles of DA-EPOCH-R with ixazomib administered twice per 21-day cycle; ixazomib maintenance was administered weekly in responders for up to 1 year...

Aim: We pooled data from three observational studies (INSIGHT MM, UVEA-IXA and REMIX) to investigate the real-world effectiveness of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory myeloma. Materials & methods: INSIGHT MM was a prospective study conducted in countries across Europe, Asia and North/Latin America while UVEA-IXA and REMIX were multicenter, retrospective/prospective studies conducted in Europe. Patients who had received IRd as ≥2nd line of therapy were analyzed...

BACKGROUND: Contractures following neonatal brachial plexus injury (NBPI) are associated with growth deficits in denervated muscles. This impairment is mediated by an increase in muscle protein degradation, as contractures can be prevented in an NBPI mouse model with bortezomib (BTZ), a proteasome inhibitor (PI). However, BTZ treatment causes substantial toxicity (0% to 80% mortality). The current study tested the hypothesis that newer-generation PIs can prevent contractures with less severe toxicity than BTZ...

Antimicrobial resistance (AMR) to currently available antibiotics/drugs is a global threat. It is desirable to develop new drugs that work through a novel target(s) to avoid drug resistance. This review discusses the potential of the caseinolytic protease P (ClpP) peptidase complex as a novel target for finding novel antibiotics, emphasising the ClpP's structure and function. ClpP contributes to the survival of bacteria via its ability to destroy misfolded or aggregated proteins. In consequence, its inhibition may lead to microbial death...

OBJECTIVES: To retrospectively analyze real-world treatment patterns in patients with relapsed/refractory multiple myeloma (RRMM) who initiated third-line treatment in Europe. METHODS: German and Italian administrative claims data were sourced from the German AOK PLUS health insurance fund and Italian local health units (2016-2020). Data for the United Kingdom (UK), France, and Spain were sourced from medical chart reviews (MCRs) from 2016 to 2018 (historical) and 2019 to 2021 (new) using electronic case report forms...

Newer methodologies are needed to assess the real-world comparative effectiveness of a "generation" of pharmaceutical innovation versus the prior standard of care. This chart review study aimed to first evaluate the cumulative clinical benefits of pharmaceutical innovation in everyday relapse/refractory multiple myeloma before analyzing findings in the context of respective real-world outcomes from the bortezomib/lenalidomide era. Study endpoints included the 52-week PFS rate in second and third line of therapy (LOT), mPFS-2 across the first and second LOT, the ORR, reasons for discontinuation, and the treatment duration per therapeutic algorithm...

Lenalidomide is a second-generation new immunomodulatory medication used to treat multiple myeloma (MM). Its mechanism of action involves affecting the expression of vascular endothelial growth factor, interleukin-6, cytochrome c , caspase-8, as well as other factors including immunological modulation and the direct killing of cells, among others, rendering it a fundamental medication, useful for the treatment of MM. Combining lenalidomide with other medications such dexamethasone, bortezomib, ixazomib, carfilzomib and daratumumab can markedly alleviate MM...

Osteolytic bone disease is present in about 80% of patients with multiple myeloma at the time of diagnosis. Managing bone disease in patients with multiple myeloma is a challenge and requires a multi-faceted treatment approach with medication, surgery, and radiation. The established treatments with intravenous or subcutaneous antiresorptives can cause debilitating adverse events for patients, mainly osteonecrosis of the jaw, which, traditionally, has been difficult to manage. Now, oral surgery is recommended and proven successful in 60-85% of patients...

The synthesis of α-haloboronic esters via atom transfer radical addition (ATRA) is constrained due to its limited range of compatible substrates or the need to manipulate the olefin coupling partners. Herein, we present a novel approach for their synthesis via Cu-catalyzed ATRA to vinyl boronic esters. The catalyst is proposed to mediate a traditionally inefficient halogen atom transfer of the α-boryl radical intermediate, thus significantly expanding the range of participating substrates relative to established methods...

PARP-1 is a crucial factor in repairing DNA single strand damage and maintaining genomic stability. However, the use of PARP-1 inhibitors is limited to combination with chemotherapy or radiotherapy, or as a single agent for indications carrying HRR defects. The ubiquitin-proteasome system processes the majority of cellular proteins and is the principal manner by which cells regulate protein homeostasis. Proteasome inhibitors can cooperate with PARP-1 inhibitors to inhibit DNA homologous recombination repair function...

In this single-center study, we aimed to describe the characteristics, treatment patterns, and outcomes of patients with multiple myeloma (MM) following treatment with bortezomib, carfilzomib, daratumumab, ixazomib, lenalidomide or pomalidomide-based regimens. Data were collected retrospectively from a study cohort of patients receiving a MM treatment in the Hospital District of Helsinki and Uusimaa (HUS) in Finland between 2016-2020. In total, 472 patients were included in the study. Median age was 68.2 years and nearly 25% had a high cytogenetic risk according to the International Myeloma Working Group categorization...

Deeper responses are associated with longer survival in multiple myeloma (MM); however, limited data exist on the impact of response kinetics on outcomes. We investigated progression-free survival (PFS) and duration of response (DOR) by response depth and in early (best confirmed response 0-4 months; n  = 424) versus late responders (best confirmed response >4 months; n  = 281). Newly diagnosed patients enrolled in TOURMALINE-MM2 receiving ixazomib-lenalidomide-dexamethasone (IRd) ( n  = 351) or placebo-Rd ( n  = 354) were evaluated post hoc ...

BACKGROUND: In multiple myeloma (MM), improving our understanding of routine clinical practice and the effectiveness of agents outside of clinical trials is important. TOURMALINE-MM1 data resulted in approval of ixazomib for MM patients who have received ≥ 1 prior therapy. PATIENTS AND METHODS: UVEA-IXA comprised a retrospective chart review in the early access program, and a prospective 1-year follow-up period. Eligible patients had had a biochemical and/or symptomatic relapse after 1-3 prior lines of therapy; no anti-MM therapy for > 3 cycles at the start of ixazomib therapy; and an Eastern Cooperative Oncology Group performance score of 0-2...

INTRODUCTION: The therapeutic targeting of the ubiquitin-proteasome pathway (UPP) through inhibitors of the 20S proteasome core proteolytic activities has revolutionized the treatment of hematological malignancies and is paving the way for its extension to solid tumors. AREAS COVERED: This review covers the progress made in the field of proteasome inhibitors, ranging from the first-generation bortezomib to the latest second-generation inhibitors such as carfilzomib and ixazomib as well as the proteasome inhibitors in clinical phase such as oprozomib and marizomib...

Aim: To compare the effectiveness of in -class transition to all-oral ixazomib-lenalidomide-dexamethasone (IRd) following parenteral bortezomib (V)-based induction versus continued V-based therapy in US oncology clinics. Patients & methods: Non-transplant eligible patients with newly diagnosed multiple myeloma (MM) receiving in-class transition to IRd (N = 100; US MM-6), or V-based therapy (N = 111; INSIGHT MM). Results: Following inverse probability of treatment weighting, overall response rate was 73...

BACKGROUND: Economic differences among currently available proteasome inhibitors (PI)-based lenalidomide-dexamethasone (Rd)-backbone triplet regimens-ixazomib (I), bortezomib (V), and carfilzomib (K) plus Rd-remain poorly understood. OBJECTIVE: To assess health care resource utilization (HCRU) and health care costs of patients with relapsed/refractory multiple myeloma (RRMM) in the United States treated with IRd, VRd, and KRd. METHODS: This retrospective longitudinal cohort study using IQVIA PharMetrics Plus adjudicated claims US data (January 1, 2015, to September 30, 2020) included adult patients with all available data who initiated IRd, VRd, or KRd in second line of therapy or later (LOT2+) on or after September 1, 2015...

In recent years, drugs that contain boronic acid groups, such as ixazomib (Ninlaro™) and bortezomib (Velcade™), have been used in the treatment of bone marrow cancer. The activity of compounds has been found to increase with the addition of boron atoms to the structure. In addition to these compounds, studies have found that fingolimod (FTY720) is more effective against breast cancer than cisplatin. Therefore, in this study, the first examples of boron-containing derivatives of fingolimod were designed and synthesized; in addition, their structures were confirmed by spectroscopic techniques...