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  • Our recent discovery M P H

    2020-03-25

    Our recent discovery (M.P., H.R., A.S.) of a highly selective and in vivo active DDR1 small-molecule inhibitor provides evidence that DDR1 is a druggable pharmaceutical target, and some details of our efforts are provided below. To avoid the repurposing of known kinase inhibitor structural motifs, we explored the chemical space offered by DNA encoded libraries (DELs). DELs employ split-and-pool combinatorial chemistry to generate large compound collections, and the technology is increasingly used by the pharmaceutical industry for the discovery of novel chemical starting points [92,93]. The effective numerical size of DEL compound collections is likely larger than that of traditional pharmaceutical-industry compound collections, and the chemical space contained within is known to be different from published chemical space [94]. Lastly, DELs are generally constructed in a target agnostic manner, and therefore unlikely to be heavily enriched with promiscuous ATP binding pocket moieties. We screened both DDR1 and DDR2, and prioritized those hit clusters that selectively enriched against DDR2; this provided us with an initial chemical starting point that was inherently selective for DDR1 over the rest of the kinome (see 2a in Fig. 4C). Starting from the moderately potent hit molecule 2a, and guided by crystal structure of DDR1 bound by 2a, we quickly developed the more potent inhibitor 2.13. However, 2.13 suffers from high clearance in microsomal preparations and required further optimization, resulting in the lead compound 2.45. The binding affinity of 2.45 for DDR1 translates into inhibition of DDR1 autophosphorylation in HT1080 cells. Additionally, 2.45 halts collagen-induced upregulation of COL1A1, COL1A2, COL3A1, FBN1 and TGBFI in renal epithelium LAF-237 synthesis in a dose-dependent manner. Col4a3−/− mice, an accepted model for both Alport Syndrome and Chronic Kidney Disease, were then treated with 2.45; the compound was found to reduce DDR1 autophosphorylation, reduce occurrence of fibrotic lesions in the kidney, and improve renal glomerular function. Our in vitro and in vivo studies with 2.45 show a clear trajectory from selective biochemical inhibition of DDR1 autophosphorylation to improvement of renal function in mice.
    Conclusion DDR1 remains one of the most attractive targets in fibrosis. Amongst the receptors present on the plasma membrane, DDR1 stands out as the major mediator of the dialogue between the intracellular and the ECM environment; this mediation occurs under both physiological and pathological conditions with regard to epithelial cell activation and repair status. The scientific evidence discussed herein indicates DDR1 as a major player of epithelial/mesenchymal cross-talk. Unfortunately, large parts of DDR1 biology remain terra incognita including unknown downstream activation pathways and the ECD shedding shutdown mechanism, these poorly understood mechanisms are likely to be an intrinsic part of DDR1 MoA and are particularly appealing areas for young investigators. Promisingly, a vast body of literature using both genetic deletion mouse models and tool compounds, suggests that once DDR1 biology is better characterized, its pharmacological inhibition should become an effective interventional strategy to prevent fibrotic lesions and/or treat established fibrotic conditions causing impaired organ function. Amongst the fibrotic diseases, chronic kidney disease, a condition affecting 10% of the global population [95], is likely to be the natural therapeutic indication for a future DDR1 inhibitor.
    Conflict of interest
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    Transparency document
    Introduction Discoidin domain receptors (DDRs) are widely expressed receptor tyrosine kinases (RTKs) that bind to and get activated by collagen(s), the major component of the extracellular matrix (Vogel et al., 1997, Shrivastava et al., 1997). There are two known members of the DDR family; namely, DDR1 and DDR2, both distinguished from other RTKs by the presence of an extracellular discoidin (DS) domain and an unusually long juxtamembrane (JM) region. DDRs have an unusually slow activation process compared to other RTKs requiring longer stimulation to achieve full scale ligand-induced tyrosine phosphorylation, the reasons behind which are not completely understood (Vogel et al., 1997, Shrivastava et al., 1997).