Discovery of JNJ-64264681: A Potent and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase.
Mark S TichenorJohn J M WienerNavin L RaoGenesis M BacaniJianmei WeiCharlotte Pooley DeckhutJ Kent BarbayKevin D KreutterLeon ChangKathleen W ClancyHeather E MurreyWeixue WangKay AhnMichael HuberElizabeth RexKevin J CoeJiejun WuHaopeng RuiKia SepassiMarcello GaudianoMariette BekkersIvo CornelissenKathryn PackmanMark J SeierstadChristos XiourasScott D BembenekRichard AlexanderCynthia MilliganSriram BalasubramanianAlec D LebsackJennifer D VenableUlrike PhilipparJames P EdwardsGavin HirstPublished in: Journal of medicinal chemistry (2022)
Bruton's tyrosine kinase (BTK) is a Tec family kinase that plays an essential role in B-cell receptor (BCR) signaling as well as Fcγ receptor signaling in leukocytes. Pharmacological inhibition of BTK has been shown to be effective in treating hematological malignancies and is hypothesized to provide an effective strategy for the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. We report the discovery and preclinical properties of JNJ-64264681 ( 13 ), a covalent, irreversible BTK inhibitor with potent whole blood activity and exceptional kinome selectivity. JNJ-64264681 demonstrated excellent oral efficacy in both cancer and autoimmune models with sustained in vivo target coverage amenable to once daily dosing and has advanced into human clinical studies to investigate safety and pharmacokinetics.
Keyphrases
- tyrosine kinase
- systemic lupus erythematosus
- epidermal growth factor receptor
- rheumatoid arthritis
- small molecule
- disease activity
- endothelial cells
- papillary thyroid
- high throughput
- multiple sclerosis
- anti inflammatory
- peripheral blood
- induced pluripotent stem cells
- squamous cell
- cell therapy
- combination therapy
- pluripotent stem cells
- interstitial lung disease
- childhood cancer
- idiopathic pulmonary fibrosis
- smoking cessation