Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors

Abdelazem, Ahmed Z.; Al-Sanea, Mohammad M.; Park, Byung Sun; Park, Hye Mi; Yoo, Kyung Ho; Sim, Taebo; Park, Jong Bae; Lee, Jun Young; Lee, So Ha

doi:10.1016/j.ejmech.2014.11.023

Cited by 15 publications

(7 citation statements)

References 18 publications

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“…Kinase Profiling is 10 dose IC 50 singlet assay. Activity of kinases were assessed by the HotSpot assay platform, which contained specific kinase/substrate pairs along with required cofactors (Abdelazem et al, 2015;Abdelazem et al, 2016;Al-Sanea et al, 2016a;Al-Sanea et al, 2015a;Al-Sanea et al, 2015b;Al-Sanea, El-Deeb & Lee, 2013;Park et al, 2014).…”

Section: In Vitro Kinase Inhibition Assaymentioning

confidence: 99%

Synthesis and biological evaluation of small molecule modulators of CDK8/Cyclin C complex with phenylaminoquinoline scaffold

Al‐Sanea

2020

PeerJ

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Background CDK8/CycC complex has kinase activity towards the carboxyterminal domain of RNA polymerase II, and contributes to the regulation of transcription via association with the mediator complex. Different human malignancies, mainly colorectal and gastric cancers, were produced as a result of overexpression of CDK8/CycC in the mediator complex. Therefore, CDK8/CycC complex represents as a cancer oncogene and it has become a potential target for developing CDK8/CycC modulators. Methods A series of nine 4-phenylaminoquinoline scaffold-based compounds 5a-i was synthesized, and biologically evaluated as potential CDK8/CycC complex inhibitors. Results The scaffold substituent effects on the intrinsic inhibitory activity toward CDK8/CycC complex are addressed trying to present a novel outlook of CDK8/CycC Complex inhibitors with 4-phenylaminoquinoline scaffold in cancer therapy. The secondary benzenesulfonamide analogues proved to be the most potent compounds in suppressing CDK8/CycC enzyme, whereas, their primary benzenesulfonamide analogues showed inferior activity. Moreover, the benzene reversed sulfonamide analogues were totally inactive. Discussion The titled scaffold showed promising inhibitory activity data and there is a crucial role of un/substituted sulfonamido group for CDK8/CycC complex inhibitory activity. Compound 5d showed submicromolar potency against CDK8/CycC (IC50 = 0.639 µM) and it can be used for further investigations and to design another larger library of phenylaminoquinoline scaffold-based analogues in order to establish detailed SARs.

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Section: In Vitro Kinase Inhibition Assaymentioning

confidence: 99%

Synthesis and biological evaluation of small molecule modulators of CDK8/Cyclin C complex with phenylaminoquinoline scaffold

Al‐Sanea

2020

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“…The 3D structure of complex ROS1 with 7c was obtained with surflex-dock. The docking mode was consistent with the literature . The partial atomic charges for the ligand atoms were calculated using the restrained electrostatic potential (RESP) protocol after structure optimization with a level of quantum mechanical treatment from the B3LYP method at the HF/6-31G* level of the Gaussian 09 suite, implemented in AmberTools12 .…”

Section: Systems and Methodsmentioning

confidence: 99%

“…In previous studies, most ROS1 inhibitors were disclosed during research aiming at other kinases inhibitors, such as crizotinib/PF-06463922 against ALK and foretinib as a c-met inhibitor. ,, Since ROS1 is a novel therapeutic target for different malignancies with high homology with ALK, few inhibitors have been identified with optimal selectivity for ROS1 relative to ALK except those studied by Lee’s team. − Furthermore, the molecular basis for the selectivity of ROS1 versus ALK still remains unclear, which hinders the rational design for a selective ROS1 inhibitor. Recently, Duker and team disclosed the subtle structural differences of their kinase domain and the selective binding site for ROS1/ALK through the systems of the foretinib and cabozantinib as selective inhibitors for ROS1 versus ALK.…”

Section: Introductionmentioning

confidence: 99%

Molecular Simulation Studies on the Binding Selectivity of Type-I Inhibitors in the Complexes with ROS1 versus ALK

Tian

Shen

et al. 2017

J. Chem. Inf. Model.

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ROS1 and ALK are promising targets of anticancer drugs for non-small-cell lung cancer. Since they have 49% amide acid sequence homology in the kinases domain and 77% identity at the ATP binding area, some ALK inhibitors also showed some significant responses for ROS1 in the clinical trial, such as the type-I binding inhibitor crizotinib and PF-06463922. As a newly therapeutic target, the selective ROS1 inhibitor is relatively rare. Moreover, the molecular basis for the selectivity of ROS1 versus ALK still remains unclear. In order to disclose the binding preference toward ROS1 over ALK and to aid the design of selective ROS1 inhibitors, the specific interactions and difference of conformational changes in the dual and selective ROS1/ALK inhibitors systems were investigated by molecular dynamics (MD) simulation and principle component analysis (PCA) in our work. Afterward, binding free energies (MM/GBSA) and binding free energies decomposition analysis indicated that the dominating effect of Van der Waals interaction drives the specific binding process of the type-I inhibitor, and residues of the P-loop and the DFG motif would play an important role in selectivity. On the basis of the modeling results, the new designed compound 14c was verified as a selective ROS1 inhibitor versus ALK, and SMU-B was a dual ROS1/ALK inhibitor by the kinase inhibitory study. These results are expected to facilitate the discovery and rational design of novel and specific ROS1 inhibitors.

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“…Kinase Profiling is 10 dose IC 50 singlet assay. Activity of kinases were assessed by the HotSpot assay platform, which contained specific kinase/substrate pairs along with required cofactors (Abdelazem et al 2015;Abdelazem et al 2016;Al-Sanea et al 2016a;Al-Sanea et al 2013;Park et al 2014).…”

Section: In Vitro Kinase Inhibition Assaymentioning

confidence: 99%

Peer Review #1 of "Synthesis and biological evaluation of small molecule modulators of CDK8/Cyclin C complex with phenylaminoquinoline scaffold (v0.1)"

2020

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Background. CDK8/CycC complex has kinase activity towards the carboxyterminal domain of RNA polymerase II, and contributes to the regulation of transcription via association with the mediator complex. Different human malignancies, mainly colorectal and gastric cancers, were produced as a result of overexpression of CDK8/CycC in the mediator complex. Therefore, CDK8/CycC complex represents as a cancer oncogene and it has become a potential target for developing CDK8/CycC modulators. Methods. A series of nine 4-phenylaminoquinoline scaffold-based compounds 5a-i were synthesized, and biological evaluation of this series was performed as potential inhibitors of CDK8/CycC complex. Results. The scaffold substituent effects on the intrinsic inhibitory activity toward CDK8/CycC complex are addressed trying to present a novel outlook of CDK8/CycC Complex inhibitors with 4phenylaminoquinoline scaffold in cancer therapy. The secondary benzenesulfonamide analogues proved to be the most potent compounds in suppressing CDK8/CycC enzyme, whereas, their primary benzenesulfonamide analogues showed inferior activity. Moreover, the benzene reversed sulfonamide analogues were totally inactive. Discussion. The titled scaffold showed promising inhibitory activity data and there is a crucial role of un/substituted sulfonamido group for CDK8/CycC complex inhibitory activity. Compound 5d showed submicromolar potency against CDK8/CycC (IC 50 = 0.639 μM) and it can be used for further investigations and to design another larger library of phenylaminoquinoline scaffold-based analogues in order to establish detailed SARs.

show abstract

Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors

Cited by 15 publications

References 18 publications

Synthesis and biological evaluation of small molecule modulators of CDK8/Cyclin C complex with phenylaminoquinoline scaffold

Synthesis and biological evaluation of small molecule modulators of CDK8/Cyclin C complex with phenylaminoquinoline scaffold

Molecular Simulation Studies on the Binding Selectivity of Type-I Inhibitors in the Complexes with ROS1 versus ALK

Peer Review #1 of "Synthesis and biological evaluation of small molecule modulators of CDK8/Cyclin C complex with phenylaminoquinoline scaffold (v0.1)"

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