Synthesis and biological evaluation of novel dasatinib analogues as potent <scp>DDR</scp>1 and <scp>DDR</scp>2 kinase inhibitors

Lü, Ling; Hussain, Muzammal; Luo, Jinfeng; Duan, Anna; Chen, Chaonan; Tu, Zhengchao; Zhang, Jiancun

doi:10.1111/cbdd.12863

Cited by 19 publications

(15 citation statements)

References 38 publications

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“…Screening of a focused library of approximately 2000 compounds originally designed as Bcr-Abl inhibitors followed by structural optimization led to the identification of a new class of DDR1 inhibitors (23). 19 Fragment-based screening of a library of 1500 compounds in combination with structural biology and computational modeling allowed identification of another class of DDR1/2 ligands [structure 24 in Supplemental Figure 5 20 ]. Lastly, virtual screening of a commercially available library of approximately 230 000 compounds was used to identify new DDR1 inhibitors [see Supplemental Figure 5 for structures 18− 25 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…To date, efforts to identify an appropriate chemical probe to modulate the activity of DDR1 in an in vivo model have been unsuccessful, largely because investigated molecules lack selectivity across the kinome. − Although an unselective profile is tolerable in a preclinical study, it is an unacceptable safety risk in a longer clinical study for a chronic treatment indication such as CKD. The challenge in creating the required selective ATP-competitive DDR1 inhibitor resides in the high homology existing in the kinase domains bound by such molecules .…”

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confidence: 99%

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DNA-Encoded Library-Derived DDR1 Inhibitor Prevents Fibrosis and Renal Function Loss in a Genetic Mouse Model of Alport Syndrome

et al. 2018

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The importance of Discoidin Domain Receptor 1 (DDR1) in renal fibrosis has been shown via gene knockout and use of antisense oligonucleotides; however, these techniques act via a reduction of DDR1 protein, while we prove the therapeutic potential of inhibiting DDR1 phosphorylation with a small molecule. To date, efforts to generate a selective small-molecule to specifically modulate the activity of DDR1 in an in vivo model have been unsuccessful. We performed parallel DNA encoded library screens against DDR1 and DDR2, and discovered a chemical series that is highly selective for DDR1 over DDR2. Structure-guided optimization efforts yielded the potent DDR1 inhibitor 2.45, which possesses excellent kinome selectivity (including 64-fold selectivity over DDR2 in a biochemical assay), a clean in vitro safety profile, and favorable pharmacokinetic and physicochemical properties. As desired, compound 2.45 modulates DDR1 phosphorylation in vitro as well as prevents collagen-induced activation of renal epithelial cells expressing DDR1. Compound 2.45 preserves renal function and reduces tissue damage in Col4a3 –/– mice (the preclinical mouse model of Alport syndrome) when employing a therapeutic dosing regime, indicating the real therapeutic value of selectively inhibiting DDR1 phosphorylation in vivo. Our results may have wider significance as Col4a3 –/– mice also represent a model for chronic kidney disease, a disease which affects 10% of the global population.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

DNA-Encoded Library-Derived DDR1 Inhibitor Prevents Fibrosis and Renal Function Loss in a Genetic Mouse Model of Alport Syndrome

et al. 2018

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“…In another study, Liu et al, synthesized novel dasatinib derivatives with potent DDR1 and DDR2 inhibitory activities [ 147 ]. One of the synthesized compounds, compound 39 ( Figure 16 A), compared with the parental dasatinib ( 1 ), demonstrated a considerably superior inhibitory potency over both DDRs and K562 cell lines (IC 50 values of 2.26 ± 0.46 nM for DDR1, 7.04 ± 2.90 nM for DDR2, and 0.125 ± 0.017 nM for K562 cell line).…”

Section: Small Molecule Ddr Kinase Inhibitorsmentioning

confidence: 99%

The Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight Against Cancer

Elkamhawy

Nada

et al. 2021

IJMS

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Discoidin domain receptor (DDR) is a collagen-activated receptor tyrosine kinase that plays critical roles in regulating essential cellular processes such as morphogenesis, differentiation, proliferation, adhesion, migration, invasion, and matrix remodeling. As a result, DDR dysregulation has been attributed to a variety of human cancer disorders, for instance, non-small-cell lung carcinoma (NSCLC), ovarian cancer, glioblastoma, and breast cancer, in addition to some inflammatory and neurodegenerative disorders. Since the target identification in the early 1990s to date, a lot of efforts have been devoted to the development of DDR inhibitors. From a medicinal chemistry perspective, we attempted to reveal the progress in the development of the most promising DDR1 and DDR2 small molecule inhibitors covering their design approaches, structure-activity relationship (SAR), biological activity, and selectivity.

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“…They showed that the DDR1 inhibitor 10 (DDR1-IN-1; DDR1 enzyme IC 50 105 nM) inhibited melanoma cell proliferation in both in vitro and ex vivo assays of hereditary Alport syndrome, tubular obstructive nephropathy and nephrotoxic serum glomerulonephritis, and was effective in animal melanoma xenograft models. Liu et al [ 27 ] reported the design and evaluation of novel dasatinib analogues as DDR1 and DDR2 inhibitors. Compound 19 was superior to dasatinib ( 7 ) against both DDRs, and demonstrated potent inhibitory activity against K562 cell lines (IC 50 values of 2.26 nM for DDR1, 7.04 nM for DDR2 and 0.125 nM for the K562 cell line).…”

Section: Selective Ddr1 Inhibitorsmentioning

confidence: 99%

Inhibitors of Discoidin Domain Receptor (DDR) Kinases for Cancer and Inflammation

Denny

Flanagan

2021

Biomolecules

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The discoidin domain receptor tyrosine kinases DDR1 and DDR2 are distinguished from other kinase enzymes by their extracellular domains, which interact with collagen rather than with peptidic growth factors, before initiating signaling via tyrosine phosphorylation. They share significant sequence and structural homology with both the c-Kit and Bcr-Abl kinases, and so many inhibitors of those kinases are also effective. Nevertheless, there has been an extensive research effort to develop potent and specific DDR inhibitors. A key interaction for many of these compounds is H-bonding to Met-704 in a hydrophobic pocket of the DDR enzyme. The most widespread use of DDR inhibitors has been for cancer therapy, but they have also shown effectiveness in animal models of inflammatory conditions such as Alzheimer’s and Parkinson’s diseases, and in chronic renal failure and glomerulonephritis.

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Synthesis and biological evaluation of novel dasatinib analogues as potent DDR1 and DDR2 kinase inhibitors

Cited by 19 publications

References 38 publications

DNA-Encoded Library-Derived DDR1 Inhibitor Prevents Fibrosis and Renal Function Loss in a Genetic Mouse Model of Alport Syndrome

DNA-Encoded Library-Derived DDR1 Inhibitor Prevents Fibrosis and Renal Function Loss in a Genetic Mouse Model of Alport Syndrome

The Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight Against Cancer

Inhibitors of Discoidin Domain Receptor (DDR) Kinases for Cancer and Inflammation

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