rolled into two groups: those who had previously received at least 2 cycles of bor - tezomib therapy and those who had received less than 2 complete cycles of bortezo - mib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression- free survival, overall survival, and safety. RESULTS The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytope - nia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treat - ment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval (CI), 15.8 to not reached), the estimated median progression- free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months. CONCLUSIONS Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1306220

Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma

Many drugs that target transforming growth factor-β (TGFβ) signalling have been developed, some of which have reached Phase III clinical trials for a number of disease applications. Preclinical and clinical studies indicate the utility of these agents in fibrosis and oncology, particularly in augmentation of existing cancer therapies, such as radiation and chemotherapy, as well as in tumour vaccines. There are also reports of specialized applications, such as the reduction of vascular symptoms of Marfan syndrome. Here, we consider why the TGFβ signalling pathway is a drug target, the potential clinical applications of TGFβ inhibition, the issues arising with anti-TGFβ therapy and how these might be tackled using personalized approaches to dosing, monitoring of biomarkers as well as brief and/or localized drug-dosing regimens.

/pdf/targeting-the-tgfb-signalling-pathway-in-disease-1wlregb4sc.pdf

Targeting the TGFβ signalling pathway in disease.

The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (KEAP1), are critical in the maintenance of redox, metabolic and protein homeostasis, as well as the regulation of inflammation. Thus, NRF2 activation provides cytoprotection against numerous pathologies including chronic diseases of the lung and liver; autoimmune, neurodegenerative and metabolic disorders; and cancer initiation. One NRF2 activator has received clinical approval and several electrophilic modifiers of the cysteine-based sensor KEAP1 and inhibitors of its interaction with NRF2 are now in clinical development. However, challenges regarding target specificity, pharmacodynamic properties, efficacy and safety remain.

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Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

Oxidative stress, mitochondrial damage and neurodegenerative diseases

The mammalian proprotein convertases constitute a family of nine secretory serine proteases that are related to bacterial subtilisin and yeast kexin. Seven of these (proprotein convertase 1 (PC1), PC2, furin, PC4, PC5, paired basic amino acid cleaving enzyme 4 (PACE4) and PC7) activate cellular and pathogenic precursor proteins by cleavage at single or paired basic residues, whereas subtilisin kexin isozyme 1 (SKI-1) and proprotein convertase subtilisin kexin 9 (PCSK9) regulate cholesterol and/or lipid homeostasis via cleavage at non-basic residues or through induced degradation of receptors. Proprotein convertases are now considered to be attractive targets for the development of powerful novel therapeutics. In this Review, we summarize the physiological functions and pathological implications of the proprotein convertases, and discuss proposed strategies to control some of their activities, including their therapeutic application and validation in selected disease states.

The biology and therapeutic targeting of the proprotein convertases

/pdf/deal-watch-abbott-boosts-investment-in-nrf2-activators-for-34p94lt2m1.pdf

Deal watch: Abbott boosts investment in NRF2 activators for reducing oxidative stress.

Preliminary Phase II trial results for REGN727 — a human proprotein convertase subtilisin/kexin type 9 (PCSK9)-specific monoclonal antibody co-developed by Regeneron and Sanofi — indicate that it effectively and safely reduces levels of low-density lipoprotein-cholesterol (LDL-C) in patients with hypercholesterolaemia undergoing statin therapy.

Trial watch: PCSK9 antibody reduces LDL cholesterol.

Metabolic disorders: Betatrophin boosts β-cells

highly successful in the treatment of both chronic myelogenous leukaemia (CML) and gastrointestinal stromal tumours (GISTs); however, it has been associated with uncommon, but severe, cardiotoxicity. Now, writing in JCI, Fernández and colleagues describe their novel approach of re-engineering imatinib to alter its kinase inhibition profile to specifically target GISTs, while reducing its toxic effects on the heart. Protein kinases are prime targets for anticancer therapies, but their close structural similarities can make achieving specificity for a particular kinase challenging, potentially leading to unwanted side effects. With this in mind, the authors aimed to redesign imatinib, focusing its specificity on C-Kit (also known as KIT) kinase inhibition (the therapeutic target for GIST) while reducing its effect on the kinase BCR–ABL (the therapeutic target for CML), which has also been linked to the cardiovascular side effects of the drug. Furthermore, they aimed to promote inhibition of JNK1, as previous research has indicated that this could ameliorate the adverse effects of imatinib on heart cells. Their methodology is based on the knowledge that protein binding sites are typically regions where it is most energetically advantageous to exclude surrounding water from the backbone hydrogen bonds. Therefore, they first set out to identify specific kinase residues within the imatinib–kinase interface that possess a local propensity for water removal. They pinpointed the residue pair C673–G676 within the imatinib–C-Kit interface, whose dehydration propensity is absent in BCR–ABL owing to differences in the local environment. Using structural and molecular dynamics analysis, they predicted that addition of a methyl group to imatinib to form the reengineered compound, WBZ_4, would promote dehydration of the C673–G676 residue pair upon binding to C-Kit and stabilize the complex, while hampering any association of WBZ_4 with BCR–ABL. Notably, this modification additionally favoured the affinity of WBZ_4 for JNK1. To confirm their theory, they screened WBZ_4 against 228 human kinases and identified selective affinities for both C-Kit and JNK1 with a 75% reduction in ABL affinity when compared with imatinib. Furthermore, in cancer cell lines, liposome-delivered WBZ_4 halted proliferation of C-Kit-expressing GIST882 cells, but, in contrast to imatinib, it had almost no effect on CML K562 cells. In a mouse model of GIST, WBZ_4 was shown to decrease tumour volume and weight to a similar extent to that observed with imatinib, but in contrast to imatinib, WBZ_4 did not affect levels of brain natriuretic peptide — a marker of myocardial hypertrophy and cardiac impairment — or affect left-ventricular cardiac function. JNK1/2 activation was reduced by WBZ_4 in mouse cardiomyocytes, contributing to the mechanistic basis for the lack of cardiotoxicity of this prototype compound. In summary, WBZ_4 could have potential as a novel therapy for GISTs, and the approach demonstrated in the study might also be applied to engineer the specificity of other kinase inhibitors with the aim of creating safer and more effective drugs.

Redesigning kinase inhibitors

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Sarah Crunkhorn

Papers

Deal watch: Abbott boosts investment in NRF2 activators for reducing oxidative stress.

Trial watch: PCSK9 antibody reduces LDL cholesterol.

Metabolic disorders: Betatrophin boosts β-cells

Redesigning kinase inhibitors

Antibacterial agents: Gallium fights infection in phase I trial