EGFR inhibitors from cancer to inflammation: Discovery of 4-fluoro-N-(4-(3-(trifluoromethyl)phenoxy)pyrimidin-5-yl)benzamide as a novel anti-inflammatory EGFR inhibitor

Elkamhawy, Ahmed; Hassan, Ahmed H.E.; Paik, Sora; Lee, Yong Sup; Lee, Hwi-Ho; Shin, Ji‐Sun; Lee, Kyung‐Tae; Roh, Eun Joo

doi:10.1016/j.bioorg.2019.01.017

Cited by 38 publications

(21 citation statements)

References 41 publications

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“…Sealed vessels with magnetic stirrers were used to perform the reactions under controlled temperature for a programmed duration. The chemical synthesis, column chromatography, NMR identification, purity, and HRMS experiments were carried out following the previously reported general methods [ 38 , 39 ] (for details, see Supplementary File ).…”

Section: Methodsmentioning

confidence: 99%

Development of New Meridianin/Leucettine-Derived Hybrid Small Molecules as Nanomolar Multi-Kinase Inhibitors with Antitumor Activity

et al. 2021

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Although the sea ecosystem offers a broad range of bioactivities including anticancer, none of the FDA-approved antiproliferative protein kinase inhibitors are derived from a marine source. In a step to develop new marine-inspired potent kinase inhibitors with antiproliferative activities, a new series of hybrid small molecules (5a–5g) was designed and synthesized based on chemical moieties derived from two marine natural products (Meridianin E and Leucettamine B). Over a panel of 14 cancer-related kinases, a single dose of 10 µM of the parent hybrid 5a possessing the benzo[d][1,3]dioxole moiety of Leucettamine B was able to inhibit the activity of FMS, LCK, LYN, and DAPK1 kinases with 82.5 ± 0.6, 81.4 ± 0.6, 75.2 ± 0.0, and 55 ± 1.1%, respectively. Further optimization revealed the most potent multiple kinase inhibitor of this new series (5g) with IC50 values of 110, 87.7, and 169 nM against FMS, LCK, and LYN kinases, respectively. Compared to imatinib (FDA-approved multiple kinase inhibitor), compound 5g was found to be ~ 9- and 2-fold more potent than imatinib over both FMS and LCK kinases, respectively. In silico docking simulation models of the synthesized compounds within the active site of FMS, LCK, LYN, and DAPK1 kinases offered reasonable explanations of the elicited biological activities. In an in vitro anticancer assay using a library of 60 cancer cell lines that include blood, lung, colon, CNS, skin, ovarian, renal, prostate, and breast cancers, it was found that compound 5g was able to suppress 60 and 70% of tumor growth in leukemia SR and renal RXF 393 cell lines, respectively. Moreover, an ADME study indicated a suitable profile of compound 5g concerning cell permeability and blood-brain barrier (BBB) impermeability, avoiding possible CNS side effects. Accordingly, compound 5g is reported as a potential lead towards novel antiproliferative marine-derived kinase modulators.

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Section: Methodsmentioning

confidence: 99%

Development of New Meridianin/Leucettine-Derived Hybrid Small Molecules as Nanomolar Multi-Kinase Inhibitors with Antitumor Activity

et al. 2021

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“…Several kinases were found to be associated with different human disorders including cancer initiation and progression. Also, the recent medicinal chemistry research targeting development of small molecule kinase inhibitors for the treatment of various diseases including cancer has been proven to be a successful strategy [33][34][35][36][37][38][39][40][41][42][43][44][45][46] . Among these cancer-related kinases, Lck was reported to be the promotor of BCR signals in chronic lymphocytic leukaemia (CLL) via catalysis of the proximal phosphorylation of CD79a and the induction of distal signalling events involving phosphorylation of Syk, activation of MAPK, NF-kB, ERK, and PI3K/ Akt signalling pathways that are responsible for CLL cell survival following BCR cross-linking.…”

Section: Lck-related Diseasesmentioning

confidence: 99%

New horizons in drug discovery of lymphocyte-specific protein tyrosine kinase (Lck) inhibitors: a decade review (2011–2021) focussing on structure–activity relationship (SAR) and docking insights

Elkamhawy

Ali

Lee

2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Lymphocyte-specific protein tyrosine kinase (Lck), a non-receptor Src family kinase, has a vital role in various cellular processes such as cell cycle control, cell adhesion, motility, proliferation, and differentiation. Lck is reported as a key factor regulating the functions of T-cell including the initiation of TCR signalling, T-cell development, in addition to T-cell homeostasis. Alteration in expression and activity of Lck results in numerous disorders such as cancer, asthma, diabetes, rheumatoid arthritis, atherosclerosis, and neuronal diseases. Accordingly, Lck has emerged as a novel target against different diseases. Herein, we amass the research efforts in literature and pharmaceutical patents during the last decade to develop new Lck inhibitors. Additionally, structure-activity relationship studies (SAR) and docking models of these new inhibitors within the active site of Lck were demonstrated offering deep insights into their different binding modes in a step towards the identification of more potent, selective, and safe Lck inhibitors.

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“…Recently, Roh's research group reported that EGFR inhibitor I , based on pyrimidine skeleton modification, inhibited LPS-induced iNOS expression and the production of IL-1β, IL-6, and TNF-α in peritoneal macrophages ( Fig. 1 ) [ 7 ]. The inhibitor weakened the activation of NF-κB through dephosphorylation of p65, inhibited the production of a variety of inflammatory factors, and thus exerted an anti-inflammatory effect.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and structure-activity relationship studies of 4-indole-2-arylaminopyrimidine derivatives as anti-inflammatory agents for acute lung injury

Chen

Wei

Zhu

et al. 2021

European Journal of Medicinal Chemistry

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Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), a clinically high mortality disease, has not been effectively treated till now, and the development of anti-acute lung injury drugs is imminent. Acute lung injury was efficiently treated by inhibiting the cascade of inflammation, and reducing the inflammatory response in the lung. A series of novel compounds with highly efficient inhibiting the expression of inflammatory factors were designed by using 4-indolyl-2-aminopyrimidine as the core skeleton. Totally eleven 4-indolyl-2-arylaminopyrimidine derivatives were designed and synthesized. As well, the related anti -ALI activity of these compounds was evaluated. Compounds 6c and 6h showed a superior activity among these compounds, and the inhibition rate of IL-6 and IL-8 release ranged from 62% to 77%, and from 65% to 72%, respectively. Furthermore, most of compounds had no significant cytotoxicity in vitro . The infiltration of inflammatory cells into lung tissue significantly reduced by using compound 6h (20 mg/kg) in the ALI mice model, which achieved the effect of protecting lung tissue and improving ALI. In addition, the inflammatory response was inhibited by using compound 6h through inhibiting phosphorylation of p-38 and ERK in MAPK signaling pathway, and resulted in protective effect on ALI. These data indicated that compound 6h showed good anti-inflammatory activity in vitro and in vivo , which was expected to become a leading compound for the treatment of ALI.

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EGFR inhibitors from cancer to inflammation: Discovery of 4-fluoro-N-(4-(3-(trifluoromethyl)phenoxy)pyrimidin-5-yl)benzamide as a novel anti-inflammatory EGFR inhibitor

Cited by 38 publications

References 41 publications

Development of New Meridianin/Leucettine-Derived Hybrid Small Molecules as Nanomolar Multi-Kinase Inhibitors with Antitumor Activity

Development of New Meridianin/Leucettine-Derived Hybrid Small Molecules as Nanomolar Multi-Kinase Inhibitors with Antitumor Activity

New horizons in drug discovery of lymphocyte-specific protein tyrosine kinase (Lck) inhibitors: a decade review (2011–2021) focussing on structure–activity relationship (SAR) and docking insights

Design, synthesis and structure-activity relationship studies of 4-indole-2-arylaminopyrimidine derivatives as anti-inflammatory agents for acute lung injury

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