Correction to Discovery of a Novel Class of Exquisitely Selective Mesenchymal-Epithelial Transition Factor (c-MET) Protein Kinase Inhibitors and Identification of the Clinical Candidate 2-(4-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol (PF-04217903) for the Treatment of Cancer

Cui, J. Jean; McTigue, Michele; Nambu, Mitchell D.; Tran-Dubé, Michelle; Pairish, Mason; Shen, Hong; Jia, Lei; Cheng, Hengmiao; Hoffman, Justin; Le, Phuong A.; Jalaie, Mehran; Goetz, Gilles H.; Koenig, Marcel; Vojkovský, Tomáš; Zhang, Fang‐Jie; Do, Steven; Botrous, Iriny; Ryan, Kevin M.; Grodsky, Neil B.; Deng, Yao; Parker, M. S.; Timofeevski, Sergei; Murray, Brion W.; Yamazaki, Shinji; Aguirre, Shirley A.; Li, Qiuhua; Zou, Helen Y.; Christensen, James G.

doi:10.1021/jm3014647

Cited by 15 publications

(51 citation statements)

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“…Type I inhibitors adopt a U-shaped conformation and bind to the ATP binding site when the kinase has a 'DFG-in' conformation ( Fig. 1A and B), in which the conserved DFG motif of the activation loop being in an 'in' conformation [11,32].…”

Section: Introductionmentioning

confidence: 99%

“…And the structureactivity relationships of the c-Met type II inhibitors to c-Met were systematically investigated based on the computationally determined binding modes. The large number of c-Met inhibitors with reported activities [9,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] as well as the six c-Met crystal structures (pdb code: 2WGJ, 2WKM, 3ZXZ, 3ZZE, 3LQ8 and 3U6I) [11,12,14,32] in complex with some of these inhibitors gave rise to the possibility to test our methods.…”

Section: Introductionmentioning

confidence: 99%

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Development of efficient docking strategies and structure-activity relationship study of the c-Met type II inhibitors

Kaas

et al. 2017

Journal of Molecular Graphics and Modelling

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Graphical AbstractTOC c-Met is a tyrosine kinase and an important therapeutic target for anticancer drugs. In present study, we systematically investigated the influence of a range of parameters on the correlation between experimental and calculated binding energies of type II c-Met inhibitors. Results from this study will form the basis for establishing an efficient computational docking approach for c-Met type II inhibitors design. Highlights• Testing a set of influences to the ranking ability of the docking program in MOE.• Structure-activity relationship study of c-Met type II inhibitors.• Establishing an efficient computational docking approach for c-Met type II inhibitors design.ABSTRACT： c-Met is a transmembrane receptor tyrosine kinase and an important therapeutic target for anticancer drugs. In the present study, we systematically investigated the influence of a range of parameters on the correlation between experimental and calculated binding free energies of type II c-Met inhibitors. We especially focused on evaluating the impact of different force fields, binding energy calculation methods, docking protocols, conformation sampling strategies, and conformations of the binding site captured in several crystallographic structures. Our results suggest that the force fields, the protein flexibility, and the selected conformation of the binding site substantially influence the correlation coefficient, while the sampling strategies and ensemble docking only mildly affect the prediction accuracy. Structure-activity relationship study suggests that the structural determinants to the high binding affinity of the type II inhibitors originate from its overall linear shape, hydrophobicity, and two conserved hydrogen bonds. Results from this study will form the basis for establishing an efficient computational docking approach for c-Met type II inhibitors design.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development of efficient docking strategies and structure-activity relationship study of the c-Met type II inhibitors

Kaas

et al. 2017

Journal of Molecular Graphics and Modelling

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“…Inhibitor 3 (SGX-523) is no longer in clinical development because of acute renal failure. 10 Without any safety concerns, the clinical study of inhibitor 4 (PF-04217903) 11 was prematurely discontinued. In addition, compounds 5 (AMG-337) 12 and 6 (INC-280) 13 were reported and have entered phase II clinical trials.…”

mentioning

confidence: 99%

“…The publicly available cocrystal structure of PF-04217903 within c-Met (PDB 3ZXZ) disclosed the binding mode of this kind of inhibitors. 11 Generally, the quinoline nitrogen atom participates in a hydrogen bond with the hinge region residue Met-1160. The N-3 nitrogen of triazolopyrazine backbone formed a hydrogen bond with Asp-1222.…”

mentioning

confidence: 99%

“…Meanwhile, triazolopyrazine backbone plays an important role in both cMet activity and kinase selectivity via the unique face-to-face π-stacking interaction with the activation loop residue Tyr-1230, and there is a positive correlation between electron deficiency of bicyclic aromatic rings and the strength of π−π interaction with Tyr-1230. 11 The substituted aryl/heteroaryl (e.g., 1-methylpyrazole) on the backbone reaches out into the solvent (Figure 2). Bioisosteric replacement is a powerful method for the identification of novel chemical series in medicinal chemistry.…”

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confidence: 99%

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Design, Synthesis, and Biological Evaluation of Novel Imidazo[1,2-a]pyridine Derivatives as Potent c-Met Inhibitors

Li¹,

Ai²,

Zhang³

et al. 2015

ACS Med. Chem. Lett.

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A series of imidazo[1,2-a]pyridine derivatives against c-Met was designed by means of bioisosteric replacement. In this study, a selective, potent c-Met inhibitor, 22e was identified, with IC 50 values of 3.9 nM against c-Met kinase and 45.0 nM against c-Met-addicted EBC-1 cell proliferation, respectively. Compound 22e inhibited c-Met phosphorylation and downstream signaling across different oncogenic forms in c-Met overactivated cancer cells and model cells. Compound 22e significantly inhibited tumor growth (TGI = 75%) with good oral bioavailability (F = 29%) and no significant hERG inhibition. On the basis of systematic metabolic study, the pathway of all possible metabolites of 22e in liver microsomes of different species has been proposed, and a major NADPH-dependent metabolite 33 was generated by liver microsomes. To block the metabolic site, 42 was designed and synthesized for further evaluation. Taken together, the imidazo[1,2-a]pyridine scaffold showed promising pharmacological inhibition of c-Met and warrants further investigation.

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Discovery of indolin-2-one derivatives as potent PAK4 inhibitors: Structure-activity relationship analysis, biological evaluation and molecular docking study

Guo

Zhu

et al. 2017

Bioorganic & Medicinal Chemistry

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Cited by 15 publications

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Development of efficient docking strategies and structure-activity relationship study of the c-Met type II inhibitors

Development of efficient docking strategies and structure-activity relationship study of the c-Met type II inhibitors

Design, Synthesis, and Biological Evaluation of Novel Imidazo[1,2-a]pyridine Derivatives as Potent c-Met Inhibitors

Discovery of indolin-2-one derivatives as potent PAK4 inhibitors: Structure-activity relationship analysis, biological evaluation and molecular docking study

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