Discovery of 2,4-diarylaminopyrimidines bearing a resorcinol motif as novel ALK inhibitors to overcome the G1202R resistant mutation

Geng, Kaijun; Xia, Zongjun; Ji, Yinchun; Zhang, Ruisi Ruthy; Sun, Deqiao; Ai, Jing; Song, Zilan; Geng, Meiyu; Zhang, Ao

doi:10.1016/j.ejmech.2017.12.060

Cited by 12 publications

(7 citation statements)

References 27 publications

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“…Thanks to the theoretical analysis tools, many pioneering works have successfully designed a number of antiresistant inhibitors to overcome drug-resistant mutations, such as L1196M, G1202R, C1156Y, etc. in ALK ,− and A421V, A156T, R155K, etc. in HCV, , which is encouraging for researches who want to use the end-point binding free energy calculation approaches for rational antiresistant drug design.…”

Section: Applications In Small-molecule Drug Designmentioning

confidence: 99%

End-Point Binding Free Energy Calculation with MM/PBSA and MM/GBSA: Strategies and Applications in Drug Design

et al. 2019

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Molecular mechanics Poisson−Boltzmann surface area (MM/PBSA) and molecular mechanics generalized Born surface area (MM/GBSA) are arguably very popular methods for binding free energy prediction since they are more accurate than most scoring functions of molecular docking and less computationally demanding than alchemical free energy methods. MM/PBSA and MM/GBSA have been widely used in biomolecular studies such as protein folding, protein−ligand binding, protein−protein interaction, etc. In this review, methods to adjust the polar solvation energy and to improve the performance of MM/PBSA and MM/GBSA calculations are reviewed and discussed. The latest applications of MM/GBSA and MM/PBSA in drug design are also presented. This review intends to provide readers with guidance for practically applying MM/PBSA and MM/GBSA in drug design and related research fields. CONTENTS 1. Introduction 9478 2. Methodology 9480 3. Assessing the Performance of MM/PBSA and MM/GBSA 9484 4. The Polar Solvation Energy and Entropy Terms in MM/PB(GB)SA Calculations 9485 4.1. The Polar Solvation Energy Term in MM/ PBSA 9485 4.2. The Polar Energy Solvation Term in MM/ GBSA 9486 4.3. Theory, Implementation, and Limitations of the Variable Dielectric Model in MM/GBSA 9487 4.4. Comparison between PB and GB 9488 4.5. Efficient Entropy Calculation Methods To Estimate the Entropy Change upon Ligand Binding 9488 5.

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Section: Applications In Small-molecule Drug Designmentioning

confidence: 99%

End-Point Binding Free Energy Calculation with MM/PBSA and MM/GBSA: Strategies and Applications in Drug Design

et al. 2019

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“…Since the G1202R mutation is located at the solvent front of the anaplastic lymphoma kinase (ALK) domain close to the inhibitor‐binding pocket, a series of new diarylaminopyrimidine analogues was designed by incorporating a resorcinol moiety or 1,2,3‐triazole moiety into the scaffolds 27 and 29 to interact with the ALK kinase domain where G1202R is located . The resulting compounds (exemplified by 28 and 30 ) showed high activity against most ALK‐resistant mutants, especially the challenging G1202R.…”

Section: Exploitation Of Solvent‐exposed Regions For Structure‐based mentioning

confidence: 99%

“…Since the G1202R mutation is located at the solvent front of the anaplastic lymphoma kinase (ALK) domain close to the inhibitor-binding pocket, a series of new diarylaminopyrimidine analogues was designed by incorporating a resorcinol moiety or 1,2,3-triazole moiety into the scaffolds 27 and 29 to interact with the ALK kinase domain where G1202R is located. [42][43][44] The resulting compounds (exemplified by 28 and 30) showed high activity against most ALK-resistant mutants, especially the challenging G1202R. In particular, compound 30 showed potent activity against a variety of frequently occurring crizotinib-resistant mutants, notably the L1196M mutant (IC 50 = 3.1 nM) identified as the "gatekeeper" mutation and the G1202R mutant (IC 50 = 8.7 nM), which confers resistance to all ALK clinical candidates.…”

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confidence: 99%

Molecular design opportunities presented by solvent‐exposed regions of target proteins

Jiang

Zhou

et al. 2019

Medicinal Research Reviews

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Solvent‐exposed regions, or solvent‐filled pockets, within or adjacent to the ligand‐binding sites of drug‐target proteins provide opportunities for substantial modifications of existing small‐molecular drug molecules without serious loss of activity. In this review, we present recent selected examples of exploitation of solvent‐exposed regions of proteins in drug design and development from the recent medicinal‐chemistry literature.

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“…ALK has received a great deal of attention as a promising therapeutic target for targeted cancer therapy and, as a result, enormous efforts have been devoted to developing ALK inhibitors. While various scaffolds such as pyrimidine, aminopyridine 8,9 , benzo[b]carbazolone 10 , indazole 11 have been exploited to identify new ALK inhibitors, 2,4-diarylamino pyrimidines 2,[12][13][14][15][16][17][18][19][20][21] have been the most common molecular platform for discovering ALK inhibitors including ceritinib and brigatinib. Crizotinib 22,23 was approved in 2011 as an ALK inhibitor for treatment of NSCLC patients harbouring EML4-ALK fusion oncogene.…”

Section: Introductionmentioning

confidence: 99%

“…In 2018, crizotinib was given a breakthrough therapy designation to treat ALK-positive relapsed/ refractory anaplastic large cell lymphoma (ALCL) [24][25][26][27] patients. However, acquired secondary mutations (L1196M, G1269A, F1174L, S1206Y, 1151 T-ins, L1152R, C1156Y and G1202R) occurring in the ALK kinase domain resulted in resistance to crizotinib 18,20,[28][29][30] . The ALK gatekeeper mutation L1196M is the most frequent secondary mutation taking place in NSCLC patients and, consequently, a significant effort has been made to identify novel and potent L1196M inhibitors 31 .…”

Section: Introductionmentioning

confidence: 99%

Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as potent ALK-L1196M inhibitors

Nam

Hwang

Kim³

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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Anaplastic lymphoma kinase (ALK) has been recognised as a promising molecular target of targeted therapy for NSCLC. We performed SAR study of pyrazolo[3,4-b]pyridines to override crizotinib resistance caused by ALK-L1196M mutation and identified a novel and potent L1196M inhibitor, 10g. 10g displayed exceptional enzymatic activities (<0.5 nM of IC 50) against ALK-L1196M as well as against ALK-wt. In addition, 10g is an extremely potent inhibitor of ROS1 (<0.5 nM of IC 50) and displays excellent selectivity over c-Met. Moreover, 10g strongly suppresses proliferation of ALK-L1196M-Ba/F3 and H2228 cells harbouring EML4-ALK via apoptosis and the ALK signalling blockade. The results of molecular docking studies reveal that, in contrast to crizotinib, 10g engages in a favourable interaction with M1196 in the kinase domain of ALK-L1196M and hydrogen bonding with K1150 and E1210. This SAR study has provided a useful insight into the design of novel and potent inhibitors against ALK gatekeeper mutant.

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Discovery of 2,4-diarylaminopyrimidines bearing a resorcinol motif as novel ALK inhibitors to overcome the G1202R resistant mutation

Cited by 12 publications

References 27 publications

End-Point Binding Free Energy Calculation with MM/PBSA and MM/GBSA: Strategies and Applications in Drug Design

End-Point Binding Free Energy Calculation with MM/PBSA and MM/GBSA: Strategies and Applications in Drug Design

Molecular design opportunities presented by solvent‐exposed regions of target proteins

Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as potent ALK-L1196M inhibitors

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