RBx10080307, a dual EGFR/IGF-1R inhibitor for anticancer therapy

Tandon, Ruchi; Senthil, V.; Nithya, D; Pamidiboina, Venu; Kumar, Ankur; Malik, Sushma; Chaira, Tridib; Diwan, Manish; Gupta, Praful; Malik, Renu; Das, Biswajit; Dastidar, Sunanda G.; Cliffe, Ian A.; Ray, Abhijit; Bhatnagar, Pradip K.

doi:10.1016/j.ejphar.2013.04.016

Cited by 8 publications

(5 citation statements)

References 21 publications

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“…Moreover, the affinity towards IGF-1R in the submicromolar range was more than thirtyfold higher than that of the corresponding 6-bromo compound 5a . Erlotinib for comparison showed no activity toward IGF-1R 26 . The 4-methoxybenzylamine function of compound 6b was less favorable than the 3-methoxybenzylamine function of derivative 6a concerning the EGFR affinity, whereas the IGF-1R affinity slightly improved.…”

Section: Methodsmentioning

confidence: 96%

Discovery of novel dual inhibitors of receptor tyrosine kinases EGFR and IGF-1R

Hempel

Totzke²,

Schächtele³

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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Novel 4-benzylamino benzo-anellated pyrrolo[2,3-b]pyridines have been synthesized with varied substitution patterns both at the molecular scaffold of the benzo-anellated ring and at the 4-benzylamino residue. With a structural similarity to substituted thieno[2,3-d]pyrimidines as epidermal growth factor receptor (EGFR) inhibitors, we characterized the inhibition of EGFR for our novel compounds. As receptor heterodimerization gained certain interest as mechanism of cancer cells to become resistant against novel protein kinase inhibitors, we additionally measured the inhibition of insulin-like growth factor receptor IGF-1R which is a prominent receptor for such heterodimerizations with EGFR. Structure–activity relationships are discussed for both kinase inhibitions depending on the varied substitution patterns. We discovered novel dual inhibitors of both receptor tyrosine kinases with interest for further studies to reduce inhibitor resistance developments in cancer treatment.

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Section: Methodsmentioning

confidence: 96%

Discovery of novel dual inhibitors of receptor tyrosine kinases EGFR and IGF-1R

Hempel

Totzke²,

Schächtele³

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…As a nal demonstration, we show that MolPAL scales well to larger virtual libraries and more than two objectives by searching the Enamine Screening Collection 45 of over 4 million molecules for those that optimize three docking objectives. The objectives were dened to identify putative dual inhibitors of IGF1R and EGFR [102][103][104] with selectivity over CYP3A4 [94][95][96]105 which could in principle serve as starting points for esophageal cancer therapeutics. To analyze performance according to the four considered evaluation metrics, we perform this search retrospectively aer docking the entire library using DOCKSTRING's protocol for each target 84 (Section 5.1).…”

Section: Molpal Scales To 3 Objectives and Larger Librariesmentioning

confidence: 99%

Pareto optimization to accelerate multi-objective virtual screening

Fromer,

Graff,

Coley

2024

Digital Discovery

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“…This compound has an IC50 of 66 nM compared to similar compound without piperazine with IC50 671. Therefore, addition of piperazin increased the activity by 10 folds [28].Based on our AI model results, piperaquin was nominated as one of the desired compounds, due to its wider presence of piperazine moiety, and previous reports on EGFR inhibition by such molecules [29], we used piperazine in this context instead. However, there is no previous report of piperazine activity alone related to EGFR and this is the first of such report, to our knowledge.…”

Section: -Piperazinmentioning

confidence: 99%

“…According to another report, salicylic acid coating on the nanoparticle efficiently improved its anti-cancer ability due to several mechanisms, including EGFR inhibition [40]. Although based on our AI model results, piperaquine was nominated as one of the compounds, due to its wider presence of the piperazine moiety, and previous reports on EGFR inhibition by such molecules [29], we used piperazine in this context instead. As stated in previous studies, analogs containing the piperazine moiety had antagonistic potency against receptors on cancer cell lines [22][23][24].…”

Section: -Conclusionmentioning

confidence: 99%

Proposing New Potential Candidates to Inhibit EGFR via Machine Learning Algorithm

Torabi

Yasami-Khiabani

Sardari

et al. 2023

Preprint

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One of the main issues in solid tumours is progressive mutation in epidermal growth factor receptors (EGFR) gene, which activates signalling pathways that create new blood vessels. In this study, it was attempted to find new a therapeutic candidate to inhibit EGFR. One of the cost-effective alternative methods to find new inhibitors has been the repositioning approach of existing drugs. The critical point of computational drug repositioning method is saving time and cost to remove the pre-clinical step and accelerate the drug discovery process. Hence, an ensemble computational-experimental approach, consisting of three different steps, a machine learning model, simulation of drug-target interaction and experimental characterization, was developed. The machine learning type used here was different tree classification method, which is one of the best randomize machine learning model to identify potential inhibitors from weak inhibitors. The machine learning step aimed to discover the approved drugs with the highest possible success rate in the experimental step. Finally, out of the nine chosen drugs, seven compounds had been confirmed to inhibit EGFR in the published articles since 2019. Hence, two identified compounds, in addition to gefitinib, as a positive control, and one neutral, were considered via molecular docking study. Finally, eight proposed drugs, including gefitinib, were investigated using MTT assay and In-Cell ELISA to characterise the drugs effect on A431 cell growth and EGFR-signaling. From our experiments, we could conclude that salicylic acid and piperazine could play an EGFR-inhibitor role like gefitinib.

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RBx10080307, a dual EGFR/IGF-1R inhibitor for anticancer therapy

Cited by 8 publications

References 21 publications

Discovery of novel dual inhibitors of receptor tyrosine kinases EGFR and IGF-1R

Discovery of novel dual inhibitors of receptor tyrosine kinases EGFR and IGF-1R

Pareto optimization to accelerate multi-objective virtual screening

Proposing New Potential Candidates to Inhibit EGFR via Machine Learning Algorithm

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