Discovery of Potent and Selective Tricyclic Inhibitors of Bruton’s Tyrosine Kinase with Improved Druglike Properties

Wang, Xiaojing; Barbosa, James A.; Blomgren, Peter; Bremer, Meire; Chen, Jacob; Crawford, James J.; Deng, Wei; Dong, Liming; Gallion, Steve; Hau, Jonathon; Hu, Huiyong; Johnson, Adam R.; Katewa, Arna; Kropf, Jeffrey E.; Lee, Seung H.; Liu, Lichuan; Lubach, Joseph W.; Macaluso, Jen; Maciejewski, Pat; Mitchell, Scott A.; Ortwine, Daniel F.; DiPaolo, Julie; Reif, Karin; Scheerens, Heleen; Schmitt, Aaron C.; Wong, Harvey; Xiong, Jin-Ming; Xu, Jianjun; Zhao, Zheng; Zhou, Fusheng; Currie, Kevin S.

doi:10.1021/acsmedchemlett.7b00103

Cited by 29 publications

(29 citation statements)

References 21 publications

(46 reference statements)

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“…In systems that involve covalent inhibition, such as in tyrosine kinases that have a conserved Cys at their active sites, it is possible to develop active site-directed covalent probes to quantify target engagement, and we have used this approach to analyze the inhibition of the Bruton’s tyrosine kinase (Btk) by the covalent inhibitor CC-292 . Btk is a nonreceptor tyrosine kinase that is a promising target for treating diseases caused by B cell dysregulation, such as B-cell malignancies and autoimmune diseases including rheumatoid arthritis and lupus. − CC-292 as well as drugs such as ibrutinib contain an acrylamide electrophile that reacts with a conserved Cys (481) in the Btk active site. We synthesized a fluorescent probe based on CC-292 that was used to quantify levels of Btk engagement by CC-292 both in cell culture (Ramos cells) as well as in B lymphocytes obtained from rats dosed with CC-292.…”

Section: In Vivo Target Vulnerability: Chemical Tools To Quantify Tar...mentioning

confidence: 99%

Drug–Target Kinetics in Drug Discovery

Tonge

2017

ACS Chem. Neurosci.

213

235

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The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation. The discovery and deployment of compounds with optimized kinetic effects requires information on the structure-kinetic relationships that modulate the kinetics of binding, and the molecular factors that control the translation of drug-target kinetics to time-dependent drug activity in the disease state. This review first introduces the potential benefits of drug-target kinetics, such as the ability to delineate both thermodynamic and kinetic selectivity, and then describes factors, such as target vulnerability, that impact the utility of kinetic selectivity. The review concludes with a description of a mechanistic PK/PD model that integrates drug-target kinetics into predictions of drug activity.

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Section: In Vivo Target Vulnerability: Chemical Tools To Quantify Tar...mentioning

confidence: 99%

Drug–Target Kinetics in Drug Discovery

Tonge

2017

ACS Chem. Neurosci.

213

235

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“…Approved BTK inhibitors have been developed for oral administration 5 . To determine oral bioavailability of the top four analogous with favourable BTK inhibitory activity, predictions regarding their absorption, distribution, metabolism, excretion, and toxicity was performed ( Supplementary Table 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…BTK is a member of the Tec-family of non-receptor tyrosine kinases and has essential roles in regulating proliferation, migration, survival, and B-cell homing 3 . The dysregulation of BTK, therefore, can lead to various haematologic malignancies 4 , 5 . However, recent studies have also implicated aberrant BTK signalling in solid cancers 6 , 7 .…”

Section: Introductionmentioning

confidence: 99%

Structure-based virtual screening and biological evaluation of novel small-molecule BTK inhibitors

Lin

Sung

Chao

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Bruton tyrosine kinase (BTK) is linked to multiple signalling pathways that regulate cellular survival, activation, and proliferation. A covalent BTK inhibitor has shown favourable outcomes for treating B cell malignant leukaemia. However, covalent inhibitors require a high reactive warhead that may contribute to unexpected toxicity, poor selectivity, or reduced effectiveness in solid tumours. Herein, we report the identification of a novel noncovalent BTK inhibitor. The binding interactions (i.e. interactions from known BTK inhibitors) for the BTK binding site were identified and incorporated into a structure-based virtual screening (SBVS). Top-rank compounds were selected and testing revealed a BTK inhibitor with >50% inhibition at 10 µM concentration. Examining analogues revealed further BTK inhibitors. When tested across solid tumour cell lines, one inhibitor showed favourable inhibitory activity, suggesting its potential for targeting BTK malignant tumours. This inhibitor could serve as a basis for developing an effective BTK inhibitor targeting solid cancers.

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“…In addition, it demonstrated similar efficacy to dexamethasone in a rat collagen-induced arthritis (CIA) model at a 25 mg/kg b.i.d. dose, confirming that it is possible to use as therapeutic agents in autoimmune diseases such as arthritis [ 60 , 61 ].…”

Section: Btkis In Clinical and Pre-clinical Evaluationsmentioning

confidence: 87%

The Development of BTK Inhibitors: A Five-Year Update

et al. 2021

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Bruton’s tyrosine kinase (BTK) represented, in the past ten years, an important target for the development of new therapeutic agents that could be useful for cancer and autoimmune disorders. To date, five compounds, able to block BTK in an irreversible manner, have been launched in the market, whereas many reversible BTK inhibitors (BTKIs), with reduced side effects that are more useful for long-term administration in autoimmune disorders, are under clinical investigation. Despite the presence in the literature of many articles and reviews, studies on BTK function and BTKIs are of great interest for pharmaceutical companies as well as academia. This review is focused on compounds that have appeared in the literature from 2017 that are able to block BTK in an irreversible or reversible manner; also, new promising tunable irreversible inhibitors, as well as PROTAC molecules, have been reported. This summary could improve the knowledge of the chemical diversity of BTKIs and provide information for future studies, particularly from the medicinal chemistry point of view. Data reported here are collected from different databases (Scifinder, Web of Science, Scopus, Google Scholar, and Pubmed) using “BTK” and “BTK inhibitors” as keywords.

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Discovery of Potent and Selective Tricyclic Inhibitors of Bruton’s Tyrosine Kinase with Improved Druglike Properties

Cited by 29 publications

References 21 publications

Drug–Target Kinetics in Drug Discovery

Drug–Target Kinetics in Drug Discovery

Structure-based virtual screening and biological evaluation of novel small-molecule BTK inhibitors

The Development of BTK Inhibitors: A Five-Year Update

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