From PIM1 to PI3Kδ via GSK3β: Target Hopping through the Kinome

Henley, Z.A.; Bax, Benjamin; Inglesby, L.M; Champigny, Aurélie C.; Gaines, Simon; Faulder, Paul; Le, Joelle; Thomas, Daniel; Washio, Yoshiaki; Baldwin, Ian R.

doi:10.1021/acsmedchemlett.7b00296

Cited by 16 publications

(24 citation statements)

References 23 publications

(46 reference statements)

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“…Henley et al [ 100 ] described a novel, potent, and selective series of 4,6-disubstituted-1 H -indazole derivatives and subsequent exploration of the structure-activity relationship led to the discovery of phosphoinositide 3-kinase delta (PI3Kδ) inhibitor for the treatment of inflammatory diseases. Among them, compound 172 showed significant PI3Kδ activity (pIC 50 = 7.0), specifically against the other PI3K isoforms (α pIC 50 = 5.0, ß pIC 50 = 5.2, γ pIC 50 = 5.2) ( Figure 53 ).…”

Section: Biological Applications Of Indazole Derivativesmentioning

confidence: 99%

Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives

2018

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Indazole-containing derivatives represent one of the most important heterocycles in drug molecules. Diversely substituted indazole derivatives bear a variety of functional groups and display versatile biological activities; hence, they have gained considerable attention in the field of medicinal chemistry. This review aims to summarize the recent advances in various methods for the synthesis of indazole derivatives. The current developments in the biological activities of indazole-based compounds are also presented.

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Section: Biological Applications Of Indazole Derivativesmentioning

confidence: 99%

Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives

2018

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“…Esses inibidores necessitam realizar interações por ligações de hidrogênio em uma importante região da enzima chamada hinge (dobradiça), como pode ser observado na Figura 1, em que o derivado pirazolo-piridínico (1) realiza ligações de hidrogênio com os resíduos Tyr134, Val135 e Glu97 da proteína cinase GSK3 beta (PDB: 5OY4). 18…”

Section: Revisãounclassified

“…Interações por ligação de hidrogênio (linhas pontilhadas amarelas) observadas entre (1) (átomos de C em branco) e os resíduos de aminoácido Tyr134, Val135 e Glu97 (átomos de C em verde) da proteína cinase GSK3β (PDB: 5OY4). 18 Distâncias em Å. Figura gerada com o programa PyMOL.…”

Section: Interações Envolvendo Cavidades-σunclassified

“…Um bom exemplo do efeito do deslocamento de moléculas de água na atividade inibitória foi mostrado no trabalho de Ritschel e colaboradores, 59 onde as interações hidrofóbicas foram um dos fatores que contribuíram para aumentar em cerca de 20 vezes a afinidade do composto (18) no sítio de ligação da t-RNA-guanina transglicosilase (TGT) em relação ao (15) devido ao efeito do deslocamento concomitante de moléculas de água pela introdução dos grupos metila e CH 2 CH 2 NH-cicloexila (Figura 18).…”

Section: Interações Hidrofóbicasunclassified

“…(15) no sítio de ligação da TGT (PDB: 2Z7K). B) Perfil de interação do composto (18) no sítio de ligação da TGT (PDB: 3EOS), cujo deslocamento de moléculas de água vistas em A aumenta a afinidade. 59 Tracejado em cinza: ligações de hidrogênio.…”

Section: Conclusõesunclassified

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Há Algo Novo No Reconhecimento Molecular Aplicado À Química Medicinal?

et al. 2020

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In Medicinal Chemistry, the knowledge, the study and the understanding of the intermolecular interactions inherent to the molecular recognition of a ligand by its target bioreceptor are essential. This is because understanding these interactions, which define the molecular complementarity between the two, is the key to analyze critically structure-activity relationship studies, allowing the optimization of the modulation of a target bioreceptor by a ligand. Thus, it is necessary the constant study and analysis of intermolecular interactions related to the ligand-bioreceptor complexes. In general, these interactions are all electrostatic in nature, being traditionally classified into two large groups, the electrostatic forces themselves (such as those present in ion-dipole or ion-ion interactions) and van der Waals forces. Despite being well known, theoretical and experimental studies have revealed an increasing number of interactions mediated by these forces. This work presents and discusses intermolecular interactions considering "classical interactions" and "new interactions" in the context of Medicinal Chemistry, taking into account their current definitions, some theoretical principles of each interaction and addressing examples in which these interactions were important for complementarity between a ligand and a biorreceptor.

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A review on synthetic strategy, molecular pharmacology of indazole derivatives, and their future perspective

Mal

Malik

Mahapatra

et al. 2022

Drug Development Research

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With different nitrogen-containing heterocyclic moieties, Indazoles earn one of the places among the top investigated molecules in medicinal research. Indazole, an important fused aromatic heterocyclic system containing benzene and pyrazole ring with a chemical formula of C 7 H 6 N 2 , is also called benzopyrazole. Indazoles consist of three tautomeric forms in which 1H-tautomers (indazoles) and 2H-tautomers (isoindazoles) exist in all phases. The tautomerism in indazoles greatly influences synthesis, reactivity, physical and even the biological properties of indazoles.The thermodynamic internal energy calculation of these tautomers points view 1H-indazole as the predominant and stable form over 2H-indazole. The natural source of indazole is limited and exists in alkaloidal nature (i.e., nigellidine, nigeglanine, nigellicine, etc.) found from Nigella plants. Some of the FDA-approved drugs like Axitinib, Entrectinib, Niraparib, Benzydamine, and Granisetron are being used to treat renal cell cancer, non-small cell lung cancer (NSCLC), epithelial ovarian cancer, chronic inflammation, chemotherapy-induced nausea, vomiting, and many more uses. Besides all these advantages regarding its biological activity, the main issue about indazoles is the less abundance in plant sources, and their synthetic derivatives also often face problems with low yield. In this review article, we discuss its chemistry, tautomerism along with their effects, different schematics for the synthesis of indazole derivatives, and their different biological activities.

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From PIM1 to PI3Kδ via GSK3β: Target Hopping through the Kinome

Cited by 16 publications

References 23 publications

Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives

Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives

Há Algo Novo No Reconhecimento Molecular Aplicado À Química Medicinal?

A review on synthetic strategy, molecular pharmacology of indazole derivatives, and their future perspective

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