REDX08608, a Novel, Potent and Selective, Reversible BTK Inhibitor with Efficacy and Equivalent Potency Against Wild-Type and Mutant C481S BTK

Guisot, Nicolas E. S.; Best, Stuart; Wright, Victoria; Thomason, Andrew G.; Woyach, Jennifer A.; Mantel, Rose; McClanahan, Fabienne; Abet, Valentina; Castagna, Diana; Cousin, Peggy; Emmerich, Juliette; Ho, Kelvin; Kelly, James Russell; King-Tours, James; Lyons, Kristina; Müller, Melanie; Refuerzo, Julienne; Sargent, Louise; Talab, Fatima; Bingham, Matilda; Phillips, Caroline; Armer, Richard

doi:10.1182/blood.v128.22.4399.4399

Cited by 4 publications

(1 citation statement)

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“…71 An interesting mode to circumvent BTK (C481S) mutations has been proposed, and involves miRNA-mediated targeting of BTK total protein, which can be achieved through HDAC inhibition. 133 Inhibitors of non-BCR related pathways, including nuclear export 134 and the para-caspase MALT1 135 together with novel small molecule inhibitors with comparable blocking activities against wild-type and C418Smutant BTK, namely ARQ531 136 and REDX08608, 137 are also currently tested in preclinical settings, with encouraging results. In addition to ibrutinib, novel small molecule BTK kinase inhibitors with higher selectivity towards BTK kinase, and less cross-reactivity with other Tec kinase family members, are currently under clinical development, including acalabrutinib, 138,139 GS-4059, 140 and BGB-3111.…”

Section: Bcr Signaling Inhibitors For Cll Treatmentmentioning

confidence: 99%

The importance of B cell receptor isotypes and stereotypes in chronic lymphocytic leukemia

2018

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B cell receptor (BCR) signaling is a central pathway promoting the survival and proliferation of normal and malignant B cells. Chronic lymphocytic leukemia (CLL) arises from mature B cells, expressing functional BCRs, mainly of IgM and IgD isotypes. Importantly, 30% of CLL patients express quasi-identical BCRs, so-called "stereotyped" receptors, indicating the existence of common antigenic determinants, which may drive disease initiation and favor its progression. Although the antigenic specificity of IgM and IgD receptors is identical, there are distinct isotypespecific responses after IgM and IgD triggering. Here, we discuss the most important steps of normal B cell development, and highlight the importance of BCR signaling for CLL pathogenesis, with a focus on differences between IgM and IgD isotype signaling. We also highlight the main characteristics of CLL patient subsets, based on BCR stereotypy, and describe subset-specific BCR function and antigen binding characteristics. Finally, we outline the key biologic and clinical responses to kinase inhibitor therapy, targeting the BCR-associated Bruton tyrosine kinase (BTK), phosphoinositide-3-kinase (PI3K), and spleen tyrosine kinase (SYK) in patients with CLL. The B cell receptor (BCR) during B cell developmentB lymphocytes develop from hematopoietic stem cells through a continuum of developmental stages that originate within the primary lymphoid tissues (i.e. fetal liver and fetal/adult marrow), with later stages of maturation occurring in secondary lymphoid organs, including the lymph nodes and the spleen (Figure 1). 1 One of the first essential steps towards maturation of a normal B cell is the successful rearrangement of immunoglobulin (Ig) heavy chain (IGH) gene segments (V, D and J segments), during a process named VDJ recombination (Figure 2), which occurs in progenitor (pro)-B cells, and leads to precursor (pre)-B-cell development. 2 During this process, a highly diverse repertoire of antigen-

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Section: Bcr Signaling Inhibitors For Cll Treatmentmentioning

confidence: 99%

The importance of B cell receptor isotypes and stereotypes in chronic lymphocytic leukemia

2018

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Targeting B Cell Signaling in Chronic Lymphocytic Leukemia

Arnason

Brown

2017

Curr Oncol Rep

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In recent years, a revolution in the management of chronic lymphocytic leukemia (CLL) has centered on the targeting of the B cell receptor (BCR) signaling pathway. Our improved understanding of the biology of cell signaling in CLL and the development of oral kinase inhibitors directed at the BCR pathway has led to the approval of two new agents and has the potential to radically change the treatment of CLL in both the relapsed/refractory and upfront settings. In this review, we will describe the underlying biology of the BCR signaling pathway. We will discuss the landmark clinical trials resulting in the approval of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and the PI3Kδ inhibitor idelalisib. We will highlight ongoing trials that are evaluating the use of combinations of these agents with standard chemotherapy. We will evaluate some of the emerging data regarding toxicity, potential off-target effects, and mechanisms of resistance to BCR signaling pathway blockade. Finally, we will highlight some of the next-generation BCR pathway inhibitors currently in development.

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AreBTKandPLCG2mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia?

Lampson

Brown

2018

Expert Review of Hematology

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Introduction: Ibrutinib is the first BTK inhibitor to show efficacy in chronic lymphocytic leukemia (CLL) and is also the first BTK inhibitor to which patients have developed resistance. Mutations in BTK and PLCG2 are found in ≈80% of CLL patients with acquired resistance to ibrutinib, but it remains unclear if these mutations are merely associated with disease relapse or directly cause it. Areas covered: Unique properties of both CLL and ibrutinib that complicate attempts to definitively conclude whether BTK/PLCG2 mutations are passengers or drivers of ibrutinib-resistant disease are reviewed. Characteristics of mutations that drive drug resistance are summarized and whether BTK/PLCG2 mutations possess these is discussed. These characteristics include (1) identification in multiple patients with acquired resistance, (2) in vitro validation of drug-resistant properties, (3) mutual exclusivity with one another, (4) increasing frequency over time on drug, and (5) high frequency at the time and site of clinical relapse. Expert Commentary: While BTK/PLCG2 mutations have characteristics suggesting that they can drive ibrutinib resistance, this conclusion remains formally unproven until specific inhibition of such mutations is shown to cause regression of ibrutinib-resistant CLL. Data suggest that alternative mechanisms of resistance do exist in some patients.

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REDX08608, a Novel, Potent and Selective, Reversible BTK Inhibitor with Efficacy and Equivalent Potency Against Wild-Type and Mutant C481S BTK

Cited by 4 publications

References 0 publications

The importance of B cell receptor isotypes and stereotypes in chronic lymphocytic leukemia

The importance of B cell receptor isotypes and stereotypes in chronic lymphocytic leukemia

Targeting B Cell Signaling in Chronic Lymphocytic Leukemia

AreBTKandPLCG2mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia?

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