2-Amino-2,3-dihydro-1<i>H</i>-indene-5-carboxamide-Based Discoidin Domain Receptor 1 (DDR1) Inhibitors: Design, Synthesis, and in Vivo Antipancreatic Cancer Efficacy

Zhu, Dongsheng; Huang, Huocong; Pinkas, Daniel; Luo, Jinfeng; Ganguly, Debolina; Fox, Alice E.; Arner, Emily N.; Xiang, Qiuping; Tu, Zheng; Bullock, Alex N.; Brekken, Rolf A.; Ding, Ke; Lu, Xiaoyun

doi:10.1021/acs.jmedchem.9b00365

Cited by 50 publications

(31 citation statements)

References 45 publications

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“… Construction of absolute pharmacophore maps. (A) The target molecule, in this case, compound 7c from Zhu et al, 54 is first modeled in complex with its target receptor using PLC descriptors and scored with BCL-AffinityNet. (B) Then, we iterate over each atom in the target molecule and sequentially remove it from the molecule to create a perturbed molecule, X.…”

Section: Resultsmentioning

confidence: 99%

“…Consider a series of type II tyrosine kinase inhibitors (TKIs) of DDR1 kinase developed recently by Zhu et al 54 We generated relative pharmacophore maps of compounds 7c, 7f, and 7j to compound 7i 54 ( Figure 9 A–D). We also modified the compound 7 scaffold to include N → C mutations in the hinge-binding region analogous to prior substitutions done by Wang et al 55 in a previous DDR1 TKI series ( Figure 9 A,E–G).…”

Section: Resultsmentioning

confidence: 99%

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General Purpose Structure-Based Drug Discovery Neural Network Score Functions with Human-Interpretable Pharmacophore Maps

Brown

Mendenhall

Geanes

et al. 2021

J. Chem. Inf. Model.

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The BioChemical Library (BCL) is an academic open-source cheminformatics toolkit comprising ligand-based virtual high-throughput screening (vHTS) tools such as quantitative structure–activity/property relationship (QSAR/QSPR) modeling, small molecule flexible alignment, small molecule conformer generation, and more. Here, we expand the capabilities of the BCL to include structure-based virtual screening. We introduce two new score functions, BCL-AffinityNet and BCL-DockANNScore, based on novel distance-dependent signed protein–ligand atomic property correlations. Both metrics are conventional feed-forward dropout neural networks trained on the new descriptors. We demonstrate that BCL-AffinityNet is one of the top performing score functions on the comparative assessment of score functions 2016 affinity prediction and affinity ranking tasks. We also demonstrate that BCL-AffinityNet performs well on the CSAR-NRC HiQ I and II test sets. Furthermore, we demonstrate that BCL-DockANNScore is competitive with multiple state-of-the-art methods on the docking power and screening power tasks. Finally, we show how our models can be decomposed into human-interpretable pharmacophore maps to aid in hit/lead optimization. Altogether, our results expand the utility of the BCL for structure-based scoring to aid small molecule discovery and design. BCL-AffinityNet, BCL-DockANNScore, and the pharmacophore mapping application, as well as the remainder of the BCL cheminformatics toolkit, are freely available with an academic license at the BCL Commons site hosted on .

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

General Purpose Structure-Based Drug Discovery Neural Network Score Functions with Human-Interpretable Pharmacophore Maps

Brown

Mendenhall

Geanes

et al. 2021

J. Chem. Inf. Model.

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“…Recently, while Zhu et al, discovered a new series of 2-amino-2,3-dihydro-1 H -indene-5-carboxamides as selective DDR1 inhibitors using a structure-based design strategy based on compound 20 [ 154 ], their efforts generated compound 51 ( Figure 21 ) which showed a unique ability to bind to the ATP-binding site of DDR1 with a K d value of 5.9 nM and an IC 50 value of 14.9 nM. In addition, compared to 20 , compound 51 had slightly lower potencies against all off-target kinases and effectively inhibited collagen-induced activation of DDR1 as well as its downstream signaling proteins.…”

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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“…Recent preclinical and clinical studies are rapidly contributing to our knowledge of the specific mechanisms by which individual tyrosine kinases contribute to cancer cell behavior. Collagen-induced DDR1 activation and epithelial–mesenchymal transition can be attenuated by the DDR1 inhibitor 7f which disrupts DDR1-PYK2-PEAK signaling in pancreatic cancer [ 251 ]. FRK inhibition attenuates aerobic glycolysis in some cancer cell models [ 23 ], while studies performed in other cancer cell models suggest FRK inhibition increases proliferation by downregulating the FRK-PTEN axis [ 252 ].…”

Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

“…For pancreatic cancer, highly specific pharmaceuticals targeting single kinases (rather than families or groups of kinases) remain underdeveloped. Currently, Bosutinib [ 80 ], 7f [ 251 ], Dapagliflozin [ 256 ], Masitinib [ 221 ], and glycofullerenes [ 257 ] have been studied as potentially useful kinase inhibitors in pancreatic cancer. Alternatively, agents such as proteolysis targeting chimeras (PROTACs) degrade—rather than inhibit—protein targets and may prove better mimics of genetic knockdown for instances in which nonenzymatic activity (e.g., activity as a ligand) underlie a kinase’s role in a particular disease [ 258 ].…”

Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Emerging Kinase Therapeutic Targets in Pancreatic Ductal Adenocarcinoma and Pancreatic Cancer Desmoplasia

Creeden

Alganem

Imami

et al. 2020

IJMS

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Kinase drug discovery represents an active area of therapeutic research, with previous pharmaceutical success improving patient outcomes across a wide variety of human diseases. In pancreatic ductal adenocarcinoma (PDAC), innovative pharmaceutical strategies such as kinase targeting have been unable to appreciably increase patient survival. This may be due, in part, to unchecked desmoplastic reactions to pancreatic tumors. Desmoplastic stroma enhances tumor development and progression while simultaneously restricting drug delivery to the tumor cells it protects. Emerging evidence indicates that many of the pathologic fibrotic processes directly or indirectly supporting desmoplasia may be driven by targetable protein tyrosine kinases such as Fyn-related kinase (FRK); B lymphoid kinase (BLK); hemopoietic cell kinase (HCK); ABL proto-oncogene 2 kinase (ABL2); discoidin domain receptor 1 kinase (DDR1); Lck/Yes-related novel kinase (LYN); ephrin receptor A8 kinase (EPHA8); FYN proto-oncogene kinase (FYN); lymphocyte cell-specific kinase (LCK); tec protein kinase (TEC). Herein, we review literature related to these kinases and posit signaling networks, mechanisms, and biochemical relationships by which this group may contribute to PDAC tumor growth and desmoplasia.

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2-Amino-2,3-dihydro-1H-indene-5-carboxamide-Based Discoidin Domain Receptor 1 (DDR1) Inhibitors: Design, Synthesis, and in Vivo Antipancreatic Cancer Efficacy

Cited by 50 publications

References 45 publications

General Purpose Structure-Based Drug Discovery Neural Network Score Functions with Human-Interpretable Pharmacophore Maps

General Purpose Structure-Based Drug Discovery Neural Network Score Functions with Human-Interpretable Pharmacophore Maps

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

Emerging Kinase Therapeutic Targets in Pancreatic Ductal Adenocarcinoma and Pancreatic Cancer Desmoplasia

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