A closer look into discoidin domain receptors lead to the development of a novel inhibitor with better anti-fibrotic effect.
Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease, where patients succumb in about three to five years after diagnosis. Currently, there are only two drugs approved by the U.S. Federal Drug Administration to treat IPF – pirfenidone and nintedanib. While both drugs can reduce the progression of IPF, its effects are limited and as a result, highlights the clear need for effective therapeutic strategies for IPF.
As discoidin domain receptors (DDRs) were previously known as potential targets for treating pulmonary fibrosis, this was further explored by a team of scientists from the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences. Led by Li Jia and Xiong Bing, the team carried out further structure modifications and developed a series of novel DDRs inhibitors with potent in vivo anti-fibrosis efficacy and low toxicity.
DDRs belong to the receptor tyrosine kinase family and have displayed the ability to delay signal transduction and sustain long-term activation. This mechanism has allowed DDRs to carry out specific biological functions in the induction of fibrosis and angiogenesis in the lungs.
In recent years, several DDR inhibitors have been reported and while these compounds have displayed good selectivity, a few of them still had strong inhibition on tumour related targets, which made them good anti-tumour inhibitors but is not appropriate for IPF treatment as that demands better security. Hence, given the importance of DDRs in pulmonary fibrosis, having selective DDR inhibitor activity would be crucial in determining its therapeutic value.
In this study, through structure-activity relationship study and computer-aided drug design, the team discovered a series of quinazoline derivatives targeting DDR2 with elevated selectivity. Through the selectivity assay against a kinase diversity panel, compound 47 was found to effectively inhibit the enzymatic activity of DDR1/2, with weak inhibitory activities against other 50-plus kinases. From this, compound 47 was selected for further assessment for safety and anti-fibrosis effects.
When compared with nintedanib, a multi-kinase inhibitor used in IPF treatment, the tolerated dose of compound 47 was substantially higher, suggesting good and better efficacy. The results of this study suggest DDR1/2 could be the IPF drug target as it plays a role in the fibrotic processes and presents compound 47 as a potential DDR inhibitor for further development. [APBN]
Source: Wang et al. (2021). Discovery of 4-cyclopropyl-3-(2-((1-cyclopropyl-1H-pyrazol-4-yl) amino) quinazolin-6-yl)-N-(3-(trifluoromethyl) phenyl) benzamides as potent discoidin domain receptor inhibitors for the treatment of idiopathic pulmonary fibrosis. Acta Pharmaceutica Sinica B.