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  • Some mechanistic experiments performed in the early

    2020-11-19

    Some mechanistic experiments performed in the early 2000s by Ongusaha et al. [78], suggest that DDR1 induction protects ddhGTP from apoptosis in a p53-dependent manner, and that impairment of DDR1 expression or function leads to a pronounced increase of DNA damage-induced apoptosis. This evidence suggests DDR1 involvement in cell and tissue repair mechanisms. The evidence from the disease models seems to suggest that DDR1 deletion or inhibition exerts its protective effect by slowing down the so called maladaptive repair originally suggested for the kidney by Joe Bonventre's group at Harvard [79]. Several lines of evidence in the last years have in fact consistently highlighted the role of epithelial cell control over myofibroblast phenotype both in vitro [80] and in vivo [81]. That would potentially explain the paracrine role of DDR1 in controlling the activation state of the resident quiescent fibroblasts. Signals in that direction have been observed by co-authors of this review (M.P., S.M., M.M.) using a highly selective DDR1 inhibitor [19] in a mouse model of glomerular injury. The use of such compound showed in fact a simultaneous reduction of the cellular proliferation of parietal epithelial cells as well as a reduction of ddhGTP ECM matrix deposition in the glomerular compartment [19].
    DDR1 as an anti-fibrotic pharmaceutical target DDR1 is an attractive anti-fibrotic target due to extensive preclinical target validation across multiple organs. Interest in DDR1 as a therapeutic target has been steadily growing, from 2 peer-reviewed DDR1 articles [20,82] available in 1993 to 32 published in 2017 (Fig. 4A). Interest from the scientific community has remained high with numerous academic, biotech and pharma industry laboratories investigating the therapeutic value of DDR1. Mining of literature with the search terms ‘discoidin domain receptor 1’ and ‘inhibition’ yields 60 publications, all published within the last 20 years, and over half of them published in the last five years. In addition to scientific publications, the term ‘DDR1’ is also observed in a growing number of patents, and eleven DDR1 crystal structures have been deposited (all in the last five years, Fig. 4A). Less stringent mining of the literature using the term ‘DDR1’ in potent web search tools such as Thomson Integrity [83] yields an impressive number of results for both scientific publications and patents (respectively 1219 and 267) in multiple indications (Fig. 4B). Unfortunately, the majority of these 1219 publications only briefly mention DDR1, and most of the 267 published patents report off-target activity on DDR1 (Google Patents search is referred here [84]). Despite this mass of scientific publications, no selective DDR1 inhibitor has entered clinical development (note that mining of clinical trial descriptions can be very misleading as marketed pan-tyrosine kinase inhibitors such as dasatinib and nilotinib commonly cite marginal off-target effects on DDR1). Since the average time for a NME to enter clinical studies is around 10–15 years [85], absence from the clinical arena (note that DDR1 was cloned 25 years ago [20]) indicates the challenge in effectively and safely drugging this receptor. Selectivity for DDR1 over the kinome, particularly its close analog DDR2, appears to be a challenging hurdle, and reported small molecule DDR1 inhibitors [86,87] generally lack selectivity. The challenge in discovering a selective DDR1 inhibitor partly resides in the limited chemical diversity used to derive new molecules. New chemical starting matter is generally recycled from existing compound collections historically enriched with known kinase inhibitor motifs. However, existing kinase inhibitors are challenging starting points toward the development of selective DDR1 inhibitors, likely because ATP binding pocket homology is highly conserved across all RTKs [88]. For example, past DDR1 inhibitors have been derived from 1.) existing tyrosine kinase inhibitors such as imatinib, nilotinib and dasatinib (see structures 1.1–1.3 in Fig. 4C) [64,87,89,90] 2.) repurposed focused compound collections originally constructed to target other kinases (see 1.4 in Fig. 4C) [87] and, 3.) commercially available compound collections necessarily enriched with known ATP binding motifs (1.5 in Fig. 4C) [91].