Bruton’s Tyrosine Kinase Inhibitors (BTKIs): Review of Preclinical Studies and Evaluation of Clinical Trials

Rozkiewicz, D; Hermanowicz, Justyna Magdalena; Kwiatkowska, Iwona; Krupa, Anna; Pawlak, Dariusz

doi:10.3390/molecules28052400

Cited by 29 publications

(18 citation statements)

References 157 publications

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“…Upregulation of BTK is now well-known to contribute to the development of multiple hematological cancers, including chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) and mast cell lymphoma (MCL), among others . BTK has consequently received considerable attention as a cancer drug target, with five small molecule inhibitors approved to date for the treatment of various blood cancers. , Despite these approved drugs proving hugely successful, there remains a desire to discover further BTK inhibitors with improved safety profiles, both as cancer therapeutics as well as treatments for diseases outside of the oncology setting, such as autoimmune and inflammatory diseases. , …”

Section: Novel Protein–ligand Interactionsmentioning

confidence: 99%

“…61 BTK has consequently received considerable attention as a cancer drug target, with five small molecule inhibitors approved to date for the treatment of various blood cancers. 60,61 Despite these approved drugs proving hugely Biochemical Lanthascreen assay with TAK1-TAB1 fusion protein in the presence of 10 μM ATP. 50 (b) Overlay of all TAK1 crystal structures available in the Protein Data Bank at the time this Perspective was written (22 structures in total).…”

Section: T H Imentioning

confidence: 99%

“…8 Screening is often described as "exploring" the "chemical space" 9,10 embodied in the molecule collection at hand. Chemical space is enormous; some estimates place the number of possible compounds with drug-like physicochemical properties to be as high as 10 60 . It is likely that the pharmacologically relevant space is smaller, due to some degree of conservation in the shape and volume of protein ligand binding sites.…”

Section: ■ Introductionmentioning

confidence: 99%

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Screening Ultra-Large Encoded Compound Libraries Leads to Novel Protein–Ligand Interactions and High Selectivity

Collie,

Clark,

Keefe

et al. 2024

J. Med. Chem.

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The DNA-encoded library (DEL) discovery platform has emerged as a powerful technology for hit identification in recent years. It has become one of the major parallel workstreams for small molecule drug discovery along with other strategies such as HTS and data mining. For many researchers working in the DEL field, it has become increasingly evident that many hits and leads discovered via DEL screening bind to target proteins with unique and unprecedented binding modes. This Perspective is our attempt to analyze reports of DEL screening with the purpose of providing a rigorous and useful account of the binding modes observed for DEL-derived ligands with a focus on binding mode novelty. ■ SIGNIFICANCEScreening DNA-encoded libraries (DELs) of small molecules has recently become one of the main technologies employed for discovering potential new drugs. Here, we analyze and discuss recent published DEL screens performed against important clinical molecular targets. Notable trends observed, including an apparent tendency for inhibitors from DEL screens to be highly selective and to adopt novel binding modes, are highlighted and discussed alongside the current state of the field and future considerations.

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Section: Novel Protein–ligand Interactionsmentioning

confidence: 99%

Section: T H Imentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Screening Ultra-Large Encoded Compound Libraries Leads to Novel Protein–Ligand Interactions and High Selectivity

Collie,

Clark,

Keefe

et al. 2024

J. Med. Chem.

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“…Inhibition of BTK disrupts signaling downstream of the B-cell receptor (BCR), a pathway on which the survival of CLL cells are dependent [3, 4]. The success of Ibrutinib has spurred the development of other BTKi including the now clinically approved BTK inhibitors: Acalabrutinib (CALQUENCE ® ), Zanubrutinib (BRUKINSA ® ), Tirabrutinib/ONO-4059 (VELEXBRU ® ), Pirtobrutinib/LOXO-405 (JAYPIRCA ® ) and Orelabrutinib (HIBRUKA ® ) [5–9]. All of the clinically approved BTKi (with the exception of Pirtobrutinib) are covalent active site inhibitors that bind to BTK C481 residue within the kinase active site.…”

Section: Introductionmentioning

confidence: 99%

“…While BTKi are highly effective in the treatment of CLL, they are also being used to treat other B-cell malignancies such as Mantle cell lymphoma (MCL), Waldenström’s macroglobulinemia, Marginal zone lymphoma (MZL) and are being evaluated in the treatment of multiple sclerosis and rheumatoid arthritis [5, 10, 11]. The plethora of clinically approved BTKi along with several other promising candidates currently in clinical trials pose a new challenge with respect to patient treatment.…”

Section: Introductionmentioning

confidence: 99%

Impact of the clinically approved BTK inhibitors on the conformation of full-length BTK and analysis of the development of BTK resistance mutations in chronic lymphocytic leukemia

Joseph,

Wales,

Jayne

et al. 2023

Preprint

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Inhibition of Bruton’s tyrosine kinase (BTK) has proven to be highly effective in the treatment of B-cell malignancies such as chronic lymphocytic leukemia (CLL), autoimmune disorders and multiple sclerosis. Since the approval of the first BTK inhibitor (BTKi), Ibrutinib, several other inhibitors including Acalabrutinib, Zanubrutinib, Tirabrutinib and Pirtobrutinib have been clinically approved. All are covalent active site inhibitors, with the exception of the reversible active site inhibitor Pirtobrutinib. The large number of available inhibitors for the BTK target creates challenges in choosing the most appropriate BTKi for treatment. Side-by-side comparisons in CLL have shown that different inhibitors may differ in their treatment efficacy. Moreover, the nature of the resistance mutations that arise in patients appears to depend on the specific BTKi administered. We have previously shown that Ibrutinib binding to the kinase active site causes unanticipated long-range effects on the global conformation of BTK (Joseph, R.E., et al., 2020,https://doi.org/10.7554/eLife.60470). Here we show that binding of each of the five approved BTKi to the kinase active site brings about distinct allosteric changes that alter the conformational equilibrium of full-length BTK. Additionally, we provide an explanation for the resistance mutation bias observed in CLL patients treated with different BTKi and characterize the mechanism of action of two common resistance mutations: BTK T474I and L528W.

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NIR‐Actuated Targeted Janus Nanomotors Remodel Immunosuppressive Tumor Microenvironment for Augmented Cancer Immunotherapy

Zhou,

Ma,

Zhang

et al. 2023

Adv Healthcare Materials

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Tumor‐associated macrophages (TAMs) always display immunosuppressive M2 phenotype in the tumor microenvironment to facilitate tumor growth, invasion and metastasis. Ibrutinib (IBR), a novel irreversible Bruton's tyrosine kinase (BTK) inhibitor, has been employed to repolarize the BTK‐overexpressed TAMs from M2 to M1 phenotype to remodel the immunosuppressive tumor microenvironment. However, the poor solubility of IBR extremely hinders its bioavailability, which results in low tumor accumulation and TAMs uptake in vivo. Herein, we proposed NIR laser‐actuated Janus nanomotors for the effective and deep delivery of IBR to TAMs in solid tumor for targeted immunotherapy. Under NIR irradiation, the Janus nanomotors exhibited efficient photothermal conversion to produce powerful propulsion via self‐thermophoresis with a speed of 12.15 μm −1s. Combined with the salic acid targeting and IBR loading, the nanomotors significantly boosted their binding and uptake efficacy by M2‐like macrophages during the active motion, which highly facilitated the reprogramming of M2 to M1 macrophages in vitro. Furtherly, the autonomous motion also validly improved in‐vivo accumulation and penetration depth in tumors to alter the M1/M2 polarization balance and activate T cells. Overall, the synthesized IC@MSA JNMs would provide a promising strategy for the efficient delivery of immunological agents toward targeted cancer immunotherapy.This article is protected by copyright. All rights reserved

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Bruton’s Tyrosine Kinase Inhibitors (BTKIs): Review of Preclinical Studies and Evaluation of Clinical Trials

Cited by 29 publications

References 157 publications

Screening Ultra-Large Encoded Compound Libraries Leads to Novel Protein–Ligand Interactions and High Selectivity

Screening Ultra-Large Encoded Compound Libraries Leads to Novel Protein–Ligand Interactions and High Selectivity

Impact of the clinically approved BTK inhibitors on the conformation of full-length BTK and analysis of the development of BTK resistance mutations in chronic lymphocytic leukemia

NIR‐Actuated Targeted Janus Nanomotors Remodel Immunosuppressive Tumor Microenvironment for Augmented Cancer Immunotherapy

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