1H and 13C NMR spectra were documented on the Bruker AV-400 spectrometer at 400 MHz and Bruker AV-500 spectrometer at 125 MHz. was forecasted to become 4.09 ?, which exceeds the limit to create a potential hydrogen connection. Desk 1 In Vitro Kinase Inhibition of Substances 6aC6k against Abl1b and DDR1a Open up in another screen < 0.001. Conclusion In conclusion, some 1, 2, 3, 4-tetrahydroisoquinoline derivatives were designed Bivalirudin Trifluoroacetate as novel selective DDR1 inhibitors highly. Substance 6j suppressed DDR1 highly, with an individual digital nM IC50 worth, nonetheless it is less potent within a -panel of 400 nonmutated kinases significantly. Thus, to the very best of our understanding, this substance represents one of the most selective DDR1 inhibitors to time. The chemical substance also demonstrated acceptable PK properties and a appealing oral therapeutic impact within a BLM-induced mouse pulmonary fibrosis model. Its solid DDR1 inhibitory strength and extraordinary focus on specificity make substance 6j not just a appealing lead substance for new medication breakthrough but FH1 (BRD-K4477) also a very important research probe for even more biological analysis of its focus on. Experimental Section General Chemistry solvents and Reagents were extracted from industrial suppliers and utilised without additional purification. Display chromatography was performed using silica gel (200C300 mesh). 1H and 13C NMR spectra had been recorded on the Bruker AV-400 spectrometer at 400 MHz and Bruker AV-500 spectrometer at 125 MHz. The reduced or high res of ESI-MS was documented with an Agilent 1200 HPLC-MSD mass spectrometer or Applied Biosystems Q-STAR Top notch ESI-LC-MS/MS mass spectrometer, respectively. The purity of substances was determined to become over 95% (>95%) by reverse-phase powerful liquid chromatography (HPLC) evaluation. HPLC device: Dionex Summit HPLC (column, Diamonsil C18, 5.0 m, 4.6 mm 250 mm (Dikma Technology); detector, PDA-100 photodiode array; injector, ASI-100 autoinjector; pump, p-680A). Elution: 85% MeOH in drinking water with 0.1% modifier (ammonia, v/v); stream price, 1.0 mL/min. Acknowledgments We enjoy the economic support in the National Organic Science Base of China (81425021 and 21572230) as well as the Organic Science Base of Guangdong Province (2015A03031201). We also thank Gemstone SOURCE OF LIGHT for beam period (proposal mx8421) aswell as the personnel of beamline I04 because of their advice about crystal assessment and data collection. The SGC is certainly a signed up charity (no. 1097737) that gets money from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, the Canada Base for Innovation, the Eshelman Institute for Innovation, Genome Canada, Innovative Medications Effort (EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen, Merck & Co., Novartis Pharma AG, Ontario Ministry of Economic Invention and Advancement, Pfizer, S?o Paulo Analysis Foundation-FAPESP, Takeda, and Wellcome Trust [092809/Z/10/Z]. Glossary Abbreviations UsedDDRdiscoidin area receptorIC50half-maximal (50%) inhibitory focus of the substanceRTKsreceptor tyrosine kinasesp38 MAPKP38 mitogen-activated proteins kinaseAblabelsonATPadenosine triphosphateTyrtyrosinePhephenylalanineMetmethionineGluglutamic acidAspaspartic acidDFGAsp-Phe-GlyMeOHmethanolPDBProtein Data Bankrtroom temperaturePd(dba)2bis certainly(dibenzylideneacetone)palladiumRuphos2-dicyclohexyl phosphino-2,6-diisopropoxy-1,1-biphenylt-BuOKpotassium tert-butanolateTHFtetrahydrofuranValvalineAlaalaninecompdcompoundsAUCarea under concentrationCtime curveT1/2half-life periodICRInstitute of Cancers ResearchSDSpragueCDawleyTmaxpeak periodCmaxpeak concentrationCLclearanceBAbioavailabilityivintravenousCDK11cyclin-dependent kinase 11EPHB8ephrin type-B receptor 8MUSKmuscle-specific receptor tyrosine kinaseTrkAnerve development aspect receptor APHLFprimary individual lung fibroblastBLMbleomycinBIDtwice dailyPKpharmacokineticPBSphosphate buffered salineSMA-smooth muscles actinH&Ehematoxylin and eosin Helping Information Obtainable The Supporting FH1 (BRD-K4477) Details is available cost-free in the ACS Magazines internet site at DOI: 10.1021/acs.jmedchem.6b00140. Artificial procedures and substance characterization, techniques, and outcomes for in vitro kinase assay, KINOMEscan, protein purification and expression, structure and crystallization determination, computational research, Western blot evaluation, animal tests, antitumor activity of substance 6j. The 1H and 13C NMR spectra of substances 6aC6k (PDF) Molecular formulation strings (CSV) Accession Rules Atomic coordinates and experimental data for the co-crystal framework of 6c with DDR1 (PDB Identification: 5FDP).It had been shown the fact that 1, 2, 3, 4-tetrahydroisoquinoline scaffold in 6c forced the pyrimidinyl moiety to look at a different dihedral position that prevented the forming of critical connections with Tyr253 and Phe382 in Abl. Moreover, the length between your atom in the pyrimidinyl Met318 and group in Abl was predicted to become 4.09 ?, which exceeds the limit to create a potential hydrogen bond. Table 1 In Vitro Kinase Inhibition of Substances 6aC6k against Abl1b and DDR1a Open in another window < 0.001. Conclusion In conclusion, a series of just one 1, 2, 3, 4-tetrahydroisoquinoline derivatives had been designed as book selective DDR1 inhibitors highly. hydrogen bond. Desk 1 In Vitro Kinase Inhibition of Substances 6aC6k against DDR1a and Abl1b Open up in another screen < 0.001. Bottom line In summary, some 1, 2, 3, 4-tetrahydroisoquinoline derivatives had been designed as book extremely selective DDR1 inhibitors. Substance 6j highly suppressed DDR1, with an individual digital nM IC50 worth, but it is certainly significantly less powerful in a -panel of 400 nonmutated kinases. Hence, to the very best of our understanding, this substance represents one of the most selective DDR1 inhibitors to time. The chemical substance also demonstrated realistic PK properties and a appealing oral therapeutic impact within a BLM-induced mouse pulmonary fibrosis model. Its solid DDR1 inhibitory strength and extraordinary focus on specificity make substance 6j not just a appealing lead substance for new medication breakthrough but also a very important research probe for further biological investigation of its target. Experimental Section General Chemistry Reagents and solvents were obtained from commercial suppliers and used without further purification. Flash chromatography was performed using silica gel (200C300 mesh). 1H and 13C NMR spectra were recorded on a Bruker AV-400 spectrometer at 400 MHz and Bruker AV-500 spectrometer at 125 MHz. The low or high resolution of ESI-MS was recorded on an Agilent 1200 HPLC-MSD mass spectrometer or Applied Biosystems Q-STAR Elite ESI-LC-MS/MS mass spectrometer, respectively. The purity of compounds was determined to be over 95% (>95%) by reverse-phase high performance liquid chromatography (HPLC) analysis. HPLC instrument: Dionex Summit HPLC (column, Diamonsil C18, 5.0 m, 4.6 mm 250 mm (Dikma Technologies); detector, PDA-100 photodiode array; injector, ASI-100 autoinjector; pump, p-680A). Elution: 85% MeOH in water with 0.1% modifier (ammonia, v/v); flow rate, 1.0 mL/min. Acknowledgments We appreciate the financial support from the National Natural Science Foundation of China (81425021 and 21572230) and the Natural Science Foundation of Guangdong Province (2015A03031201). We also thank Diamond Light Source for beam time (proposal mx8421) as well as the staff of beamline I04 for their assistance with crystal testing and data collection. The SGC is a registered charity (no. 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, the Canada Foundation for Innovation, the Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen, Merck & Co., Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, S?o Paulo Research Foundation-FAPESP, Takeda, and Wellcome Trust [092809/Z/10/Z]. Glossary Abbreviations UsedDDRdiscoidin domain receptorIC50half-maximal (50%) inhibitory concentration of a substanceRTKsreceptor tyrosine kinasesp38 MAPKP38 mitogen-activated protein kinaseAblabelsonATPadenosine triphosphateTyrtyrosinePhephenylalanineMetmethionineGluglutamic acidAspaspartic acidDFGAsp-Phe-GlyMeOHmethanolPDBProtein Data Bankrtroom temperaturePd(dba)2bis(dibenzylideneacetone)palladiumRuphos2-dicyclohexyl phosphino-2,6-diisopropoxy-1,1-biphenylt-BuOKpotassium tert-butanolateTHFtetrahydrofuranValvalineAlaalaninecompdcompoundsAUCarea under concentrationCtime curveT1/2half-life periodICRInstitute of Cancer ResearchSDSpragueCDawleyTmaxpeak timeCmaxpeak concentrationCLclearanceBAbioavailabilityivintravenousCDK11cyclin-dependent kinase 11EPHB8ephrin type-B receptor 8MUSKmuscle-specific receptor tyrosine kinaseTrkAnerve growth factor receptor APHLFprimary human lung fibroblastBLMbleomycinBIDtwice dailyPKpharmacokineticPBSphosphate buffered salineSMA-smooth muscle actinH&Ehematoxylin and eosin Supporting Information Available The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.6b00140. Synthetic procedures and compound characterization, procedures, and results for in vitro kinase assay, KINOMEscan, protein expression and purification, crystallization and structure determination, computational study, Western blot analysis, animal experiments, antitumor activity of compound 6j. The 1H and 13C NMR spectra of compounds 6aC6k (PDF) Molecular formula strings (CSV) Accession Codes Atomic coordinates and experimental data for the co-crystal structure of 6c with DDR1 (PDB ID: 5FDP) will be released upon article publication. Author Contributions Z. Wang, H. Bian, and S. G. Bartual contributed equally to this work. Notes The authors declare no competing financial interest. Supplementary Material jm6b00140_si_001.pdf(4.8M, pdf) jm6b00140_si_003.csv(1.6K, csv).The purity of compounds was determined to be over 95% (>95%) by reverse-phase high performance liquid chromatography (HPLC) analysis. shown that the 1, 2, 3, 4-tetrahydroisoquinoline scaffold in 6c forced the pyrimidinyl moiety to adopt a different dihedral angle that prevented the formation of critical interactions with Tyr253 and Phe382 in Abl. Moreover, the distance between the atom in the pyrimidinyl group and Met318 in Abl was predicted to be 4.09 ?, which exceeds the limit to form a potential hydrogen bond. Table 1 In Vitro Kinase Inhibition of Compounds 6aC6k against DDR1a and Abl1b Open in a separate window < 0.001. Conclusion In summary, a series of 1, 2, 3, 4-tetrahydroisoquinoline derivatives were designed as novel highly selective DDR1 inhibitors. Compound 6j strongly suppressed DDR1, with a single digital nM IC50 value, but it is significantly less potent in a panel of 400 nonmutated kinases. Thus, to the best of our knowledge, this compound represents one of the most selective DDR1 inhibitors to time. The chemical substance also demonstrated acceptable PK properties and a appealing oral therapeutic impact within a BLM-induced mouse pulmonary fibrosis model. Its solid DDR1 inhibitory strength and extraordinary focus on specificity make substance 6j not just a appealing lead substance for brand-new medication breakthrough but a very important analysis probe also for further natural analysis of its focus on. Experimental Section General Chemistry Solvents and Reagents were extracted from industrial suppliers and utilised without further purification. Display chromatography was performed using silica gel (200C300 mesh). 1H and 13C NMR spectra had been recorded on the Bruker AV-400 spectrometer at 400 MHz and Bruker AV-500 spectrometer at 125 MHz. The reduced or high res of ESI-MS was documented with an Agilent 1200 HPLC-MSD mass spectrometer or Applied Biosystems Q-STAR Top notch ESI-LC-MS/MS mass spectrometer, respectively. The purity of substances was determined to become over 95% (>95%) by reverse-phase powerful liquid chromatography (HPLC) evaluation. HPLC device: Dionex Summit HPLC (column, Diamonsil C18, 5.0 m, 4.6 mm 250 mm (Dikma Technology); detector, PDA-100 photodiode array; injector, ASI-100 autoinjector; pump, p-680A). Elution: 85% MeOH in drinking water with 0.1% modifier (ammonia, v/v); stream price, 1.0 mL/min. Acknowledgments We enjoy the economic support in the National Organic Science Base of China (81425021 and 21572230) as well as the Organic Science Base of Guangdong Province (2015A03031201). We also thank Gemstone SOURCE OF LIGHT for beam period (proposal mx8421) aswell as the personnel of beamline I04 because of their advice about crystal assessment and data collection. The SGC is normally a signed up charity (no. 1097737) that gets money from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, the Canada Base for Innovation, the Eshelman Institute for Innovation, Genome Canada, Innovative Medications Effort (EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen, Merck & Co., Novartis Pharma AG, Ontario Ministry of Economic Advancement and Technology, Pfizer, S?o Paulo Analysis Foundation-FAPESP, Takeda, and Wellcome Trust [092809/Z/10/Z]. Glossary Abbreviations UsedDDRdiscoidin domains receptorIC50half-maximal (50%) inhibitory focus of the substanceRTKsreceptor tyrosine kinasesp38 MAPKP38 mitogen-activated proteins kinaseAblabelsonATPadenosine triphosphateTyrtyrosinePhephenylalanineMetmethionineGluglutamic acidAspaspartic acidDFGAsp-Phe-GlyMeOHmethanolPDBProtein Data Bankrtroom temperaturePd(dba)2bis normally(dibenzylideneacetone)palladiumRuphos2-dicyclohexyl phosphino-2,6-diisopropoxy-1,1-biphenylt-BuOKpotassium tert-butanolateTHFtetrahydrofuranValvalineAlaalaninecompdcompoundsAUCarea under concentrationCtime curveT1/2half-life periodICRInstitute of Cancers ResearchSDSpragueCDawleyTmaxpeak periodCmaxpeak concentrationCLclearanceBAbioavailabilityivintravenousCDK11cyclin-dependent kinase 11EPHB8ephrin type-B receptor 8MUSKmuscle-specific receptor tyrosine kinaseTrkAnerve development aspect receptor APHLFprimary individual lung fibroblastBLMbleomycinBIDtwice dailyPKpharmacokineticPBSphosphate buffered salineSMA-smooth muscles actinH&Ehematoxylin and eosin Helping Information Obtainable The Supporting Details is available cost-free over the ACS Magazines internet site at DOI: 10.1021/acs.jmedchem.6b00140. Artificial procedures and substance characterization, techniques, and outcomes for in vitro kinase assay, KINOMEscan, proteins appearance and purification, crystallization and framework determination, computational research, Western blot evaluation, animal tests, antitumor activity of substance 6j. The 1H and 13C NMR spectra of substances 6aC6k (PDF) Molecular formulation strings (CSV) Accession Rules Atomic coordinates and experimental data for the co-crystal framework of 6c with DDR1 (PDB Identification: 5FDP) will end up being released upon content publication. Author Efforts Z. Wang, H. Bian, and S. G. Bartual added equally to the work. Records The authors declare no contending financial curiosity. Supplementary Materials jm6b00140_si_001.pdf(4.8M, pdf) jm6b00140_si_003.csv(1.6K, csv).The 1H and 13C NMR spectra of compounds 6aC6k (PDF) Molecular formula strings (CSV) Accession Codes Atomic coordinates and experimental data for the co-crystal structure of 6c with DDR1 (PDB Identification: 5FDP) will end up being released upon article publication. Author Contributions Z. ?, which exceeds the limit to create a potential hydrogen connection. Desk 1 In Vitro Kinase Inhibition of Substances 6aC6k against DDR1a and Abl1b Open up in another screen < 0.001. Bottom line In summary, some 1, 2, 3, 4-tetrahydroisoquinoline derivatives had been designed as book extremely selective DDR1 inhibitors. Substance 6j highly suppressed DDR1, with an individual digital nM IC50 worth, but it is normally significantly less potent in a panel of 400 nonmutated kinases. Therefore, to the best of our knowledge, this compound represents probably one of the most selective DDR1 inhibitors to day. The compound also demonstrated sensible PK properties and a encouraging oral therapeutic effect inside a BLM-induced mouse pulmonary fibrosis model. Its strong DDR1 inhibitory potency and extraordinary target specificity make compound 6j not only a encouraging lead compound for new drug finding but also a valuable research probe for further biological investigation of its target. Experimental Section General Chemistry Reagents and solvents were obtained from commercial suppliers and used without further purification. Adobe flash chromatography was performed using silica gel (200C300 mesh). 1H and 13C NMR spectra were recorded on a Bruker AV-400 spectrometer at 400 MHz and Bruker AV-500 spectrometer at 125 MHz. The low or high resolution of ESI-MS was recorded on an Agilent 1200 HPLC-MSD mass spectrometer or Applied Biosystems Q-STAR Elite ESI-LC-MS/MS mass spectrometer, respectively. The purity of compounds was determined to be over 95% (>95%) by reverse-phase high performance liquid chromatography (HPLC) analysis. HPLC instrument: Dionex Summit HPLC (column, Diamonsil C18, 5.0 m, 4.6 mm 250 mm (Dikma Systems); detector, PDA-100 photodiode array; injector, ASI-100 autoinjector; pump, p-680A). Elution: 85% MeOH in water with 0.1% modifier (ammonia, v/v); circulation rate, 1.0 mL/min. Acknowledgments We value the monetary support from your National Natural Science Basis of China (81425021 and 21572230) and the Natural Science Basis of Guangdong Province (2015A03031201). We also thank Diamond Light Source for beam time (proposal mx8421) as well as the staff of beamline I04 for his or her assistance with crystal screening and data collection. The SGC is definitely a authorized charity (no. 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, the Canada Basis for Innovation, the Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen, Merck & Co., Novartis Pharma AG, Ontario FH1 (BRD-K4477) Ministry of Economic Development and Advancement, Pfizer, S?o Paulo Study Foundation-FAPESP, Takeda, and Wellcome Trust [092809/Z/10/Z]. Glossary Abbreviations UsedDDRdiscoidin website receptorIC50half-maximal (50%) inhibitory concentration of a substanceRTKsreceptor tyrosine kinasesp38 MAPKP38 mitogen-activated protein kinaseAblabelsonATPadenosine triphosphateTyrtyrosinePhephenylalanineMetmethionineGluglutamic acidAspaspartic acidDFGAsp-Phe-GlyMeOHmethanolPDBProtein Data Bankrtroom temperaturePd(dba)2bis definitely(dibenzylideneacetone)palladiumRuphos2-dicyclohexyl phosphino-2,6-diisopropoxy-1,1-biphenylt-BuOKpotassium tert-butanolateTHFtetrahydrofuranValvalineAlaalaninecompdcompoundsAUCarea under concentrationCtime curveT1/2half-life periodICRInstitute of Malignancy ResearchSDSpragueCDawleyTmaxpeak timeCmaxpeak concentrationCLclearanceBAbioavailabilityivintravenousCDK11cyclin-dependent kinase 11EPHB8ephrin type-B receptor 8MUSKmuscle-specific receptor tyrosine kinaseTrkAnerve growth element receptor APHLFprimary human being lung fibroblastBLMbleomycinBIDtwice dailyPKpharmacokineticPBSphosphate buffered salineSMA-smooth muscle mass actinH&Ehematoxylin and eosin Assisting Information Available The Supporting Info is available free of charge within the ACS Publications site at DOI: 10.1021/acs.jmedchem.6b00140. Synthetic procedures and compound characterization, methods, and results for in vitro kinase assay, KINOMEscan, protein manifestation and purification, crystallization and structure determination, computational study, Western blot analysis, animal experiments, antitumor activity of compound 6j. The 1H and 13C NMR spectra of compounds 6aC6k (PDF) Molecular method strings (CSV) Accession Codes Atomic coordinates and experimental data for the co-crystal structure of 6c with DDR1 (PDB ID: 5FDP) will become released upon article publication. Author Contributions Z. Wang, H. Bian, and S. G. Bartual contributed.Its strong DDR1 inhibitory potency and extraordinary target specificity make compound 6j not only a promising lead compound for new drug finding but also a valuable research probe for further biological investigation of its target. Experimental Section General Chemistry Reagents and solvents were obtained from commercial suppliers and used without further purification. inhibitor 6c was superimposed in to the Abl framework (PDB Identification: 3IK3) (Body ?Figure22E). It had been shown the fact that 1, 2, 3, 4-tetrahydroisoquinoline scaffold in 6c compelled the pyrimidinyl moiety to look at a different dihedral position that prevented the forming of important connections with Tyr253 and Phe382 in Abl. Furthermore, the distance between your atom in the pyrimidinyl group and Met318 in Abl was forecasted to become 4.09 ?, which exceeds the limit to create a potential hydrogen connection. Desk 1 In Vitro Kinase Inhibition of Substances 6aC6k against DDR1a and Abl1b Open up in another home window < 0.001. Bottom line In summary, some 1, 2, 3, 4-tetrahydroisoquinoline derivatives had been designed as book extremely selective DDR1 inhibitors. Substance 6j highly suppressed DDR1, with an individual digital nM IC50 worth, but it is certainly significantly less powerful in a -panel of 400 nonmutated kinases. Hence, to the very best of our understanding, this substance represents perhaps one of the most selective DDR1 inhibitors to time. The chemical substance also demonstrated realistic PK properties and a appealing oral therapeutic impact within a BLM-induced mouse pulmonary fibrosis model. Its solid DDR1 inhibitory strength and extraordinary focus on specificity make substance 6j not just a guaranteeing lead substance for new medication breakthrough but also a very important research probe for even more biological analysis of its focus on. Experimental Section General Chemistry Reagents and solvents had been obtained from industrial suppliers and utilised without further purification. Display chromatography was performed using silica gel (200C300 mesh). 1H and 13C NMR spectra had been recorded on the Bruker AV-400 spectrometer at 400 MHz and Bruker AV-500 spectrometer at 125 MHz. The reduced or high res of ESI-MS was documented with an Agilent 1200 HPLC-MSD mass spectrometer or Applied Biosystems Q-STAR Top notch ESI-LC-MS/MS mass spectrometer, respectively. The purity of substances was determined to become over 95% (>95%) by reverse-phase powerful liquid chromatography (HPLC) evaluation. HPLC device: Dionex Summit HPLC (column, Diamonsil C18, 5.0 m, 4.6 mm 250 mm (Dikma Technology); detector, PDA-100 photodiode array; injector, ASI-100 autoinjector; pump, p-680A). Elution: 85% MeOH in drinking water with 0.1% modifier (ammonia, v/v); movement price, 1.0 mL/min. Acknowledgments We enjoy the economic support through the National Organic Science Base of China (81425021 and 21572230) as well as the Organic Science Base of Guangdong Province (2015A03031201). We also thank Gemstone SOURCE OF LIGHT for beam period (proposal mx8421) aswell as the personnel of beamline I04 because of their advice about crystal tests and data collection. The SGC is certainly a signed up charity (no. 1097737) that gets money from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, the Canada Base for Innovation, the Eshelman Institute for Innovation, Genome Canada, Innovative Medications Effort (EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen, Merck & Co., Novartis Pharma AG, Ontario Ministry of Economic Advancement and Invention, Pfizer, S?o Paulo Analysis Foundation-FAPESP, Takeda, and Wellcome Trust [092809/Z/10/Z]. Glossary Abbreviations UsedDDRdiscoidin area receptorIC50half-maximal (50%) inhibitory focus of the substanceRTKsreceptor tyrosine kinasesp38 MAPKP38 mitogen-activated proteins kinaseAblabelsonATPadenosine triphosphateTyrtyrosinePhephenylalanineMetmethionineGluglutamic acidAspaspartic acidDFGAsp-Phe-GlyMeOHmethanolPDBProtein Data Bankrtroom temperaturePd(dba)2bis certainly(dibenzylideneacetone)palladiumRuphos2-dicyclohexyl phosphino-2,6-diisopropoxy-1,1-biphenylt-BuOKpotassium tert-butanolateTHFtetrahydrofuranValvalineAlaalaninecompdcompoundsAUCarea under concentrationCtime curveT1/2half-life periodICRInstitute of Tumor ResearchSDSpragueCDawleyTmaxpeak periodCmaxpeak concentrationCLclearanceBAbioavailabilityivintravenousCDK11cyclin-dependent kinase 11EPHB8ephrin type-B receptor 8MUSKmuscle-specific receptor tyrosine kinaseTrkAnerve development aspect receptor APHLFprimary individual lung fibroblastBLMbleomycinBIDtwice dailyPKpharmacokineticPBSphosphate buffered salineSMA-smooth muscle tissue actinH&Ehematoxylin and eosin Helping Information Obtainable The Supporting Details is available cost-free in the ACS Magazines internet site at DOI: 10.1021/acs.jmedchem.6b00140. Artificial procedures and substance characterization, techniques, and outcomes for in vitro kinase assay, KINOMEscan, proteins appearance and purification, crystallization and framework determination, computational research, Western blot evaluation, animal tests, antitumor activity of substance 6j. The 1H and 13C NMR spectra of substances 6aC6k (PDF) Molecular formulation strings (CSV) Accession Rules Atomic coordinates and experimental data for the co-crystal framework of 6c with DDR1 (PDB Identification: 5FDP) will end up being released upon content publication. Author Efforts Z. Wang, H. Bian, and S. G. Bartual added equally to the work. Records The authors declare no contending financial curiosity. Supplementary Materials jm6b00140_si_001.pdf(4.8M, pdf) jm6b00140_si_003.csv(1.6K, csv).