Investigation of Janus Kinase (JAK) Inhibitors for Lung Delivery and the Importance of Aldehyde Oxidase Metabolism

Abstract

The Janus family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) play an essential role in the receptor signaling of cytokines that have been implicated in the pathogenesis of severe asthma, and there is emerging interest in the development of smallmolecule-inhaled JAK inhibitors as treatments. Here, we describe the optimization of a quinazoline series of JAK inhibitors and the results of mouse lung pharmacokinetic (PK) studies where only low concentrations of parent compound were observed. Subsequent investigations revealed that the low exposure was due to metabolism by aldehyde oxidase (AO), so we sought to identify quinazolines that were not metabolized by AO. We found that specific substituents at the quinazoline 2-position prevented AO metabolism and this was rationalized through computational docking studies in the AO binding site, but they compromised kinome selectivity. Results presented here highlight that AO metabolism is a potential issue in the lung.

Comparative Anticancer Potentials of Taxifolin and Quercetin Methylated Derivatives against HCT-116 Cell Lines: Effects of O-Methylation on Taxifolin and Quercetin as Preliminary Natural Leads

“…The crystal structures of the pro- and antiapoptotic proteins with PDB ID: 1NW9, 3H0E, 4HY5, 4QVX, , and 7Q7I, representing caspase-9, caspase-3, cIAP1 BIR3, Bcl-xl, STAT3, and JAK2, were downloaded from the Research Collaboratory for Structural Bioinformatics (RCSB) protein data bank. The structures of the methylated flavonoids of P. jaubertii were obtained from the PubChem database .…”

Transfer Learning Enhanced Graph Neural Network for Aldehyde Oxidase Metabolism Prediction and Its Experimental Application

“…𝑖𝑛ℎ𝑖𝑏𝑖𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑖𝑜 = 1 − 𝐴 𝑊 𝐴 𝑂 (12) where 𝐴 𝑊 and 𝐴 𝑜 refer to the peak area of oxidative metabolite in human liver cytosol with inhibitor and without inhibitor, respectively.…”

“…The copyright holder for this preprint (which this version posted June 7, 2023. ; https://doi.org/10.1101/2023.06.05.543711 doi: bioRxiv preprint such as carbazeran, BIBX1382, FK3453, JNJ-38877605, and Lu AF09535 [9][10][11]. These drugs are mainly kinase inhibitors, as their structures generally include nitrogen-containing heterocycles as an important binding motif, making them more likely to be liable to AOXmediated metabolism [12][13][14]. Given the enormous losses caused by clinical development failures, it is essential to thoroughly evaluate AOX-mediated metabolism in the early drug discovery process.…”

Transfer learning enhanced graph neural network for aldehyde oxidase metabolism prediction and its experimental application

“…It has contributed to the clinical failure of many novel agents, such as carbazeran, BIBX1382, FK3453, JNJ-38877605, and Lu AF09535 11 , 12 , 13 . These drugs are mainly kinase inhibitors, as their structures generally include nitrogen-containing heterocycles as important binding motifs, making them more likely to be liable to AOX-mediated metabolism 14 , 15 , 16 . Given the enormous losses caused by clinical development failures, it is essential to thoroughly evaluate AOX-mediated metabolism in the early drug discovery process 17 .…”