Optimization of novel reversible Bruton’s tyrosine kinase inhibitors identified using Tethering-fragment-based screens

Hopkins, Brian T.; Bame, Eris; Bell, Noah; Bohnert, Tonika; Bowden-Verhoek, Jon K.; Bui, Minna; Cancilla, Mark T.; Conlon, Patrick R.; Cullen, Patrick; Erlanson, Daniel A.; Fan, Junfa; Fuchs-Knotts, Tarra; Hansen, Steven G.; Heumann, Stacey A.; Jenkins, Tracy J.; Marcotte, D.J.; McDowell, Bob; Mertsching, Elisabeth; Negrou, Ella; Otipoby, Kevin L.; Poreci, Urjana; Romanowski, M.J.; Scott, Daniel A.; Silvian, Laura; Yang, Wenjin; Zhong, Min

doi:10.1016/j.bmc.2019.05.021

Cited by 16 publications

(7 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The initial hit pyrrolopyrimidine 5 (BTK IC 50 = 3700 nM, Figure 2) was identified from Biogen's internal proprietary screening collection. 31 It was cocrystallized with the BTK protein to obtain a structure to 1.4 Å resolution (Figure 3, Supplementary Table S-1). Compound 5 is an orthosteric ATP-competitive inhibitor that binds to the BTK in a DFG-in conformation.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of BIIB068: A Selective, Potent, Reversible Bruton’s Tyrosine Kinase Inhibitor as an Orally Efficacious Agent for Autoimmune Diseases

Bohnert

Otipoby

et al. 2020

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

Autoreactive B cell-derived antibodies form immune complexes that likely play a pathogenic role in autoimmune diseases. In systemic lupus erythematosus (SLE), these antibodies bind Fc receptors on myeloid cells and induce proinflammatory cytokine production by monocytes and NETosis by neutrophils. Bruton’s tyrosine kinase (BTK) is a non-receptor tyrosine kinase that signals downstream of Fc receptors and plays a transduction role in antibody expression following B cell activation. Given the roles of BTK in both the production and sensing of autoreactive antibodies, inhibitors of BTK kinase activity may provide therapeutic value to patients suffering from autoantibody-driven immune disorders. Starting from an in-house proprietary screening hit followed by structure-based rational design, we have identified a potent, reversible BTK inhibitor, BIIB068 (1), which demonstrated good kinome selectivity with good overall drug-like properties for oral dosing, was well tolerated across preclinical species at pharmacologically relevant doses with good ADME properties, and achieved >90% inhibition of BTK phosphorylation (pBTK) in humans.

show abstract

Section: ■ Introductionmentioning

confidence: 99%

Discovery of BIIB068: A Selective, Potent, Reversible Bruton’s Tyrosine Kinase Inhibitor as an Orally Efficacious Agent for Autoimmune Diseases

Bohnert

Otipoby

et al. 2020

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…It is inevitable and unfortunate that the necessity to define strict criteria for inclusion in the table leads to a number of "near-misses". These can still be interesting, inspiring, and pioneering FBDD stories, and 2019 examples include inhibitors of protein−protein interactions, 9 protein−DNA interactions, 10,11 bacterial targets 12 including bacterial quorum sensing, 13 sepiapterin reductase, 14 Glyoxalase 1, 15 Bruton's tyrosine kinase, 16 and the CXCR4 chemokine receptor. 17 Candidate articles for inclusion in Table 1 were identified as described in detail in previous perspectives.…”

mentioning

confidence: 99%

Fragment-to-Lead Medicinal Chemistry Publications in 2019

Jahnke

Erlanson²,

Esch

et al. 2020

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

Fragment-based drug discovery (FBDD) has grown and matured to a point where it is valuable to keep track of its extent and details of application. This Perspective summarizes successful fragment-to-lead stories published in 2019. It is the fifth in a series that started with literature published in 2015. The analysis of screening methods, optimization strategies, and molecular properties of hits and leads are presented in the hope of informing best practices for FBDD. Moreover, FBDD is constantly evolving, and the latest technologies and emerging trends are summarized. These include covalent FBDD, FBDD for the stabilization of proteins or protein–protein interactions, FBDD for enzyme activators, new screening technologies, and advances in library design and chemical synthesis.

show abstract

“…While the sub-atomic objective of QL47 isn't known, almost certainly, this compound focuses on a host factor that is engaged with the interpretation of a particular subset of emissary RNAs, including viral RNAs (Hopkins et al, 2019;Zou et al, 2016). Liang et al sought after a correlative way to deal with recognize intensi ies that target have factors that are fundamental for viral replication and opinioned that the expected favourable position of this methodology is that viral obstruction may develop all the more gradually in light of the fact that there is definitely not an immediate course to viral opposition emerging from transformations that square drugof icial to a viral objective (Liang et al, 2017).…”

Section: Resultsmentioning

confidence: 99%

Awareness About Medical Applications Of Ql-47 Among Dental Students

Masilamani

Ganapathy

2020

ijrps

View full text Add to dashboard Cite

QL47 a Bruton Tyrosine Kinase inhibitor is a host-targeted, small molecule antiviral that inhibits steady-state viral protein expression. This small molecule broadly inhibits both viral and host protein synthesis and targets a translation step specific to eukaryotic cells and has the potential to be used as an antiviral medication. The aim of the study was to assess the awareness about medical applications of QL-47 among dental students. This was a questionnaire-based cross-sectional type of study comprising 100 dental college students in Chennai. A self-designed questionnaire with ten questions eliciting the knowledge and awareness about QL 47 therapy among dental college students. Questionnaires were circulated through an online website survey planets questions explored the awareness on QL 47 therapy, indications, contraindications, mechanism of action and side effects. After the responses were received from 100 participants, data were collected and analysed.5% were aware about QL 47 therapy. 3% were aware of the mechanism of action of QL 47 therapy. 4% were aware of the indications of QL 47 therapy. 3% were aware of the QL 47 therapy.3%.were aware of the side effects of QL 47 therapy. The awareness about QL 47 in medical applications and managing viral infections was less among dental students. Increased awareness and educational programs should be initiated to spread knowledge about QL 47 therapy.

show abstract

Optimization of novel reversible Bruton’s tyrosine kinase inhibitors identified using Tethering-fragment-based screens

Cited by 16 publications

References 59 publications

Discovery of BIIB068: A Selective, Potent, Reversible Bruton’s Tyrosine Kinase Inhibitor as an Orally Efficacious Agent for Autoimmune Diseases

Discovery of BIIB068: A Selective, Potent, Reversible Bruton’s Tyrosine Kinase Inhibitor as an Orally Efficacious Agent for Autoimmune Diseases

Fragment-to-Lead Medicinal Chemistry Publications in 2019

Awareness About Medical Applications Of Ql-47 Among Dental Students

Contact Info

Product

Resources

About