In This Issue, Volume 12, Issue 5

Discovery of a Potent and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase with Oral Anti-Inflammatory Activity

Bruton’s tyrosine kinase (BTK) is involved in signaling pathways of B-cells and Fc receptors and therefore plays a role in B cell activation and inflammation. As such, modulation of BTK can modulate both adaptive and innate immune responses, and inhibition of BTK is proposed to be an excellent strategy for treating autoimmune diseases such as rheumatoid arthritis (RA). Although BTK inhibitors have been approved for use in various cancers, they have not yet been approved for treatment of RA or other autoimmune disease indications.

In their Letter (10.1021/acsmedchemlett.1c00044), Tichenor, Rao, and colleagues from Janssen report the conversion of an ATP-competitive inhibitor with micromolar affinity into a potent and selective covalent BTK inhibitor. Specifically, introduction of an acrylamide warhead to engage a nearby noncatalytic cysteine residue, a tailoring of hydrophobic contacts, and leveraging atropoisomeric-specific optimization ultimately delivered a compound with excellent inhibitory kinetics, minimal off-target kinase interactions, and a sufficient in vivo pharmacokinetic profile for a covalent target engagement strategy. Preclinical efficacy was established in a collagen-induced arthritis model in rats, and appropriate target exposure/efficacy goals were met. Overall, this work establishes a new lead series of novel BTK inhibitors for further medicinal chemistry optimization.

Development of Fluorescence Imaging Probes for Labeling COX-1 in Live Ovarian Cancer Cells

Cyclooxygenases (COXs) regulate prostaglandin and thromboxane biosynthesis and thus play an essential role in regulating inflammation. Though the inducible isoform COX-2 has been targeted by therapeutics for decades, the constitutively expressed isoform COX-1 has received less attention despite its emerging role as a cancer biomarker and possible therapeutic target.

In this issue, Wuest and colleagues from the University of Alberta exploit computer-aided drug design tools and previous structure–activity relationship studies to identify a novel class of 3-furyl-substituted-1-aryl pyrazoles as COX-1 inhibitors (10.1021/acsmedchemlett.1c00065). The optimized inhibitor displays submicromolar potency and >1000-fold selectivity for COX-1 as well as inhibitory activity in COX-1-expressing ovarian cancer cells. Further, attachment of an isobenzoxadiazole fluorophore delivered a tool compound useful for imaging COX-1 expression in cellular assays. Ultimately, the lead inhibitor and fluorescent probe should be useful for exploring COX-1-related cancer pharmacology.

Radiosynthesis and Biological Evaluation of [¹⁸F]R91150, a Selective 5-HT_2A Receptor Antagonist for PET-Imaging

The serotonergic 5-HT_2A receptor has been implicated in many neurological disorders, including depression, anxiety, schizophrenia, and Alzheimer’s and Parkinson’s diseases. Subsequently, 5-HT_2A has been targeted in search of anxiolytic, antidepressant, and antipsychotic drugs. Such campaigns greatly benefit from positron emission tomography (PET) tracers to demonstrate in vivo receptor engagement, though previous radioligands for the 5-HT_2A have displayed poor physicochemical properties, insufficient in vivo stability, short radiochemical half-lives, and/or have been prepared in insufficiently low radiochemical yields to provide sufficient material for translational studies.

In their Letter (10.1021/acsmedchemlett.0c00658), Neumaier and coworkers from the Jülich Research Centre report an improved synthesis of the 5HT_2A selective ligand [¹⁸F]R91150. The key step in the sequence involves a Cu-mediated fluorination of the corresponding pinacol boronoate ester, and subsequent deprotection of an aniline delivers the labeled product in good radiochemical yield and specific activity. Further, in rat brain slices, the radiotracer displayed selective ex vivo engagement of 5-HT_2A receptors, and further optimization of the radiosynthesis should provide sufficient quantity of material for in vivo human imaging and possibly clinical application.