A New Smoothened Antagonist Bearing the Purine Scaffold Shows Antitumour Activity In Vitro and In Vivo

Zárate, Alejandro; Espinosa‐Bustos, Christian; Guerrero, Simón; Fierro, Angélica; Oyarzún-Ampuero, Felipe; Quest, Andrew F. G.; Loricchio, Elena; Caimano, Miriam; Calcaterra, Andrea; González-Quiroz, Matías; Aguirre, Adam; Meléndez, Jaime; Salas, Cristian O.

doi:10.3390/ijms22168372

Cited by 12 publications

(5 citation statements)

References 78 publications

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“…In this work, continuing our program to develop 2,6,9-trisubstituted purine derivatives with antitumoral activity [44][45][46][47], we report a new set of 31 purine derivatives with interesting effects on Bcr-Abl, BTK and FLT3-ITD activities. In the design of our compounds, we considered our previous results and the chemical structures of the purine-based kinase inhibitors (Figure 3).…”

Section: Introductionmentioning

confidence: 96%

Design, Synthesis, In Silico Studies and Inhibitory Activity towards Bcr-Abl, BTK and FLT3-ITD of New 2,6,9-Trisubstituted Purine Derivatives as Potential Agents for the Treatment of Leukaemia

et al. 2022

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We report 31 new compounds designed, synthesized and evaluated on Bcr-Abl, BTK and FLT3-ITD as part of our program to develop 2,6,9-trisubstituted purine derivatives as inhibitors of oncogenic kinases. The design was inspired by the chemical structures of well-known kinase inhibitors and our previously developed purine derivatives. The synthesis of these purines was simple and used a microwave reactor for the final step. Kinase assays showed three inhibitors with high selectivity for each protein that were identified: 4f (IC50 = 70 nM for Bcr-Abl), 5j (IC50 = 0.41 μM for BTK) and 5b (IC50 = 0.38 μM for FLT-ITD). The 3D-QSAR analysis and molecular docking studies suggested that two fragments are potent and selective inhibitors of these three kinases: a substitution at the 6-phenylamino ring and the length and volume of the alkyl group at N-9. The N-7 and the N-methyl-piperazine moiety linked to the aminophenyl ring at C-2 are also requirements for obtaining the activity. Furthermore, most of these purine derivatives were shown to have a significant inhibitory effect in vitro on the proliferation of leukaemia and lymphoma cells (HL60, MV4-11, CEM, K562 and Ramos) at low concentrations. Finally, we show that the selected purines (4i, 5b and 5j) inhibit the downstream signalling of the respective kinases in cell models. Thus, this study provides new evidence regarding how certain chemical modifications of purine ring substituents provide novel inhibitors of target kinases as potential anti-leukaemia drugs.

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Section: Introductionmentioning

confidence: 96%

Design, Synthesis, In Silico Studies and Inhibitory Activity towards Bcr-Abl, BTK and FLT3-ITD of New 2,6,9-Trisubstituted Purine Derivatives as Potential Agents for the Treatment of Leukaemia

et al. 2022

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“…The cytotoxicity of the synthesized heterocyclic quinones was evaluated against BPC‐3, AsPC‐1 and MIA‐PaCa‐2 pancreatic cancer cell lines [52] . For this purpose, the cytotoxicity of the compounds was measured using the known MTT colorimetric assay [53–55] . To determine IC 50 values, which represent the necessary concentration of a compound required for 50 % in vitro inhibition following 72 h of sustained exposure to the test compounds, serial dilutions (from 0.1 to 25, 50 or 100 μM, depending on solubility) for each compound were evaluated in triplicate, using gemcitabine as a reference drug.…”

Section: Resultsmentioning

confidence: 99%

Phenoxy‐ and Phenylamino‐Heterocyclic Quinones: Synthesis and Preliminary Anti‐Pancreatic Cancer Activity

Sánchez

Salas

Gallardo-Fuentes

et al. 2022

Chemistry & Biodiversity

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The successful application of fragment‐based drug discovery strategy for the efficient synthesis of phenoxy‐ or phenylamino‐2‐phenyl‐benzofuran, ‐benzoxazole and ‐benzothiazole quinones is described. Interestingly, in the final step of the synthesis of the target compounds, unusual results were observed on the regiochemistry of the reaction of bromoquinones with phenol and aniline. A theoretical study was carried out for better understanding the factors that control the regiochemistry of these reactions. The substituted heterocyclic quinones were evaluated in vitro to determine their cytotoxicity by the MTT method in three pancreatic cancer cell lines (MIA‐PaCa‐2, BxPC‐3, and AsPC‐1). Phenoxy benzothiazole quinone 26a showed potent cytotoxic activity against BxPC‐3 cell lines, while phenylamino benzoxazole quinone 20 was the most potent on MIA‐PaCa‐2 cells. Finally, electrochemical properties of these quinones were determined to correlate with a potential mechanism of action. All these results, indicate that the phenoxy quinone fragment led to compounds with increased activity against pancreatic cancer cells.

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“…Recent studies have expanded upon structural components of Vismodegib that have resulted in more effective therapeutics and attenuation of resistance [ 98 , 99 ]. One study identified two new molecules as potent SMO inhibitors that are loosely founded upon the structure of Vismodegib.…”

Section: Chemotherapies That Target Hedgehog Signalingmentioning

confidence: 99%

Modulation of Hedgehog Signaling for the Treatment of Basal Cell Carcinoma and the Development of Preclinical Models

Dukes

Meade

2022

Biomedicines

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Basal Cell Carcinoma (BCC) is the most commonly diagnosed cancer worldwide. While the survivability of BCC is high, many patients are excluded from clinically available treatments due to health risks or personal choice. Further, patients with advanced or metastatic disease have severely limited treatment options. The dysregulation of the Hedgehog (Hh) signaling cascade drives onset and progression of BCC. As such, the modulation of this pathway has driven advancements in BCC research. In this review, we focus firstly on inhibitors that target the Hh pathway as chemotherapeutics against BCC. Two therapies targeting Hh signaling have been made clinically available for BCC patients, but these treatments suffer from limited initial efficacy and a high rate of chemoresistant tumor recurrence. Herein, we describe more recent developments of chemical scaffolds that have been designed to hopefully improve upon the available therapeutics. We secondly discuss the history and recent efforts involving modulation of the Hh genome as a method of producing in vivo models of BCC for preclinical research. While there are many advancements left to be made towards improving patient outcomes with BCC, it is clear that targeting the Hh pathway will remain at the forefront of research efforts in designing more effective chemotherapeutics as well as relevant preclinical models.

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A New Smoothened Antagonist Bearing the Purine Scaffold Shows Antitumour Activity In Vitro and In Vivo

Cited by 12 publications

References 78 publications

Design, Synthesis, In Silico Studies and Inhibitory Activity towards Bcr-Abl, BTK and FLT3-ITD of New 2,6,9-Trisubstituted Purine Derivatives as Potential Agents for the Treatment of Leukaemia

Design, Synthesis, In Silico Studies and Inhibitory Activity towards Bcr-Abl, BTK and FLT3-ITD of New 2,6,9-Trisubstituted Purine Derivatives as Potential Agents for the Treatment of Leukaemia

Phenoxy‐ and Phenylamino‐Heterocyclic Quinones: Synthesis and Preliminary Anti‐Pancreatic Cancer Activity

Modulation of Hedgehog Signaling for the Treatment of Basal Cell Carcinoma and the Development of Preclinical Models

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