Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors

Wang, Zhen; Bian, Hui; Bartual, S.G.; Du, Wenting; Luo, Jinfeng; Zhao, Haitao; Zhang, Shasha; Cheng, Ming‐Jen; Zhou, Yang; Xu, Yong; Tu, Zhengchao; Ren, Xiaomei; Lu, Xiaoyun; Brekken, Rolf A.; Yao, Libo; Bullock, Alex N.; Su, Jin; Ding, Ke

doi:10.1021/acs.jmedchem.6b00140

Cited by 52 publications

(65 citation statements)

References 28 publications

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“…For the development of kinase chemical probes for cell biology research, kinase inhibitors must display sufficient intracellular selectivity at the intended target ( Arrowsmith et al., 2015 ). We applied the energy transfer technique to query affinity and selectivity of the novel chemical probe 6j ( Figure S3 ), a putative selective inhibitor for DDR1 ( Wang et al., 2016 ). In biochemical measurements using the truncated domain of DDR1, 6j demonstrates 20-fold selectivity over DDR2 ( Wang et al., 2016 ).…”

Section: Resultsmentioning

confidence: 99%

“…We applied the energy transfer technique to query affinity and selectivity of the novel chemical probe 6j ( Figure S3 ), a putative selective inhibitor for DDR1 ( Wang et al., 2016 ). In biochemical measurements using the truncated domain of DDR1, 6j demonstrates 20-fold selectivity over DDR2 ( Wang et al., 2016 ). However, as shown in Figure S3 , this selectivity index was considerably lower in cells, suggesting that phenotypic responses may arise from inhibition of a combination of both DDR1 and DDR2.…”

Section: Resultsmentioning

confidence: 99%

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Quantitative, Wide-Spectrum Kinase Profiling in Live Cells for Assessing the Effect of Cellular ATP on Target Engagement

Vasta

Corona

Wilkinson

et al. 2018

Cell Chemical Biology

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228

274

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SummaryFor kinase inhibitors, intracellular target selectivity is fundamental to pharmacological mechanism. Although a number of acellular techniques have been developed to measure kinase binding or enzymatic inhibition, such approaches can fail to accurately predict engagement in cells. Here we report the application of an energy transfer technique that enabled the first broad-spectrum, equilibrium-based approach to quantitatively profile target occupancy and compound affinity in live cells. Using this method, we performed a selectivity profiling for clinically relevant kinase inhibitors against 178 full-length kinases, and a mechanistic interrogation of the potency offsets observed between cellular and biochemical analysis. For the multikinase inhibitor crizotinib, our approach accurately predicted cellular potency and revealed improved target selectivity compared with biochemical measurements. Due to cellular ATP, a number of putative crizotinib targets are unexpectedly disengaged in live cells at a clinically relevant drug dose.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Quantitative, Wide-Spectrum Kinase Profiling in Live Cells for Assessing the Effect of Cellular ATP on Target Engagement

Vasta

Corona

Wilkinson

et al. 2018

Cell Chemical Biology

Self Cite

228

274

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“…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%

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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“…ABL2 signaling regulates fibroblast proliferation [ 72 ]. DDR1 inhibitors reduce fibrosis in other fibrotic diseases [ 73 , 74 , 75 , 76 ]. FYN regulates downstream serine-threonine kinase activities involved in the modulation of fibroblast–epithelial cell interactions and the promotion of organ fibrosis [ 77 , 78 ].…”

Section: Discussionmentioning

confidence: 99%

Kinome Array Profiling of Patient-Derived Pancreatic Ductal Adenocarcinoma Identifies Differentially Active Protein Tyrosine Kinases

Creeden

Alganem

Imami

et al. 2020

IJMS

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Pancreatic cancer remains one of the most difficult malignancies to treat. Minimal improvements in patient outcomes and persistently abysmal patient survival rates underscore the great need for new treatment strategies. Currently, there is intense interest in therapeutic strategies that target tyrosine protein kinases. Here, we employed kinome arrays and bioinformatic pipelines capable of identifying differentially active protein tyrosine kinases in different patient-derived pancreatic ductal adenocarcinoma (PDAC) cell lines and wild-type pancreatic tissue to investigate the unique kinomic networks of PDAC samples and posit novel target kinases for pancreatic cancer therapy. Consistent with previously described reports, the resultant peptide-based kinome array profiles identified increased protein tyrosine kinase activity in pancreatic cancer for the following kinases: epidermal growth factor receptor (EGFR), fms related receptor tyrosine kinase 4/vascular endothelial growth factor receptor 3 (FLT4/VEGFR-3), insulin receptor (INSR), ephrin receptor A2 (EPHA2), platelet derived growth factor receptor alpha (PDGFRA), SRC proto-oncogene kinase (SRC), and tyrosine kinase non receptor 2 (TNK2). Furthermore, this study identified increased activity for protein tyrosine kinases with limited prior evidence of differential activity in pancreatic cancer. These protein tyrosine kinases include B lymphoid kinase (BLK), Fyn-related kinase (FRK), Lck/Yes-related novel kinase (LYN), FYN proto-oncogene kinase (FYN), lymphocyte cell-specific kinase (LCK), tec protein kinase (TEC), hemopoietic cell kinase (HCK), ABL proto-oncogene 2 kinase (ABL2), discoidin domain receptor 1 kinase (DDR1), and ephrin receptor A8 kinase (EPHA8). Together, these results support the utility of peptide array kinomic analyses in the generation of potential candidate kinases for future pancreatic cancer therapeutic development.

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Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors

Cited by 52 publications

References 28 publications

Quantitative, Wide-Spectrum Kinase Profiling in Live Cells for Assessing the Effect of Cellular ATP on Target Engagement

Quantitative, Wide-Spectrum Kinase Profiling in Live Cells for Assessing the Effect of Cellular ATP on Target Engagement

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

Kinome Array Profiling of Patient-Derived Pancreatic Ductal Adenocarcinoma Identifies Differentially Active Protein Tyrosine Kinases

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