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Computational high-throughput screening and in vitro approaches identify CB-006-3;A novel PI3K-BRAF^(V600E) dual targeted inhibitor against melanoma

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Oncology Research 2021年第5期29卷 305-318页

作者： FAISAL HASSAN TOBEIGEI reem mgahtani AHMAD SHAIKH AMER AL ALI NADER KAMELI HOSSAM KAMLI PRASANNA RAJAGOPALAN Department of Dermatology College of MedicineKing Khalid UniversityAbhaSaudi Arabia Department of Clinical Laboratory Sciences College of Applied Medical SciencesKing Khalid UniversityAbhaSaudi Arabia Department of Clinical Laboratory Sciences Faculty of Applied Medical SciencesUniversity of BishaAl NakhilBishaSaudi Arabia Department of Medical Laboratory Technology Faculty of Applied Medical SciencesJazan UniversityJazanSaudi Arabia Medical Research Center Jazan UniversityJazanSaudi Arabia Central Research Laboratory College of Applied Medical SciencesKing Khalid UniversityAbhaSaudi Arabia

Malignant melanoma is characterized by both genetic and molecular alterations that activate phosphoinositide 3-kinase(PI3K),and RAS/BRAF *** this work,through diversity-based high-throughput virtual screening we identified a lead molecule that selectively targets PI3K and BRAF^(V600E) *** screening,Molecular dynamics simulation and MMPBSA calculations were ***3K and BRAF^(V600E) kinase inhibition was done.A375 and G-361 cells were used for in vitro cellular analysis to determine antiproliferative effects,annexin V binding,nuclear fragmentation and cell cycle *** screening of small molecules indicates compound CB-006-3 selectively targets PI3KCG(gamma subunit),PI3KCD(delta subunit)and BRAF^(V600E).Molecular dynamics simulation and MMPBSA bases binding free energy calculations predict a stable binding of CB-006-3 to the active sites of PI3K and BRAF^(V600E).The compound effectively inhibited PI3KCG,PI3KCD and BRAF^(V600E)kinases with respective IC50 values of 75.80,160.10 and 70.84 ***-006-3 controlled the proliferation of A375 and G-361 cells with GI50 values of 223.3 and 143.6 nM,respectively.A dose dependent increase in apoptotic cell population and sub G0/G1 phase of cell cycle were also observed with the compound treatment in addition to observed nuclear fragmentation in these ***,CB-006-3 inhibited BRAF^(V600E),PI3KCD and PI3KCG in both melanoma ***,based on the computational modeling and in vitro validations,we propose CB-006-3 as a lead candidate for selectively targeting PI3K and mutant BRAF^(V600E) to inhibit melanoma cell *** experimental validations,including pharmacokinetic evaluations in mouse models will identify the druggability of the proposed lead candidate for further development as a therapeutic agent for treating melanoma.

关键词： PI3K BRAF/RAS BRAF^(V600E) Melanoma High-throughput screening

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Anticancer efficacy of 3-(4-isopropyl)benzylidene-8-ethoxy,6-methyl,chroman-4-one(SBL-060),a novel,dual,estrogen receptor-Akt kinase inhibitor in acute myeloid leukemia cells

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Oncology Research 2021年第3期29卷 149-157页

作者： MESFER AL SHAHRANI PRASANNA RAJAGOPALAN MOHAMMAD ABOHASSAN MOHAMMAD ALSHAHRANI YASSER ALRAEY reem mgahtani SURESH RADHAKRISHNAN KHLOOD DAGREERY Department of Clinical Laboratory Sciences College of Applied Medical SciencesKing Khalid UniversityAbhaSaudi Arabia Central Research Laboratory College of Applied Medical SciencesKing Khalid UniversityAbhaSaudi Arabia PG and Research Department of Chemistry Presidency CollegeChennaiTamil NaduIndia Regional Laboratory and Central Blood Bank JazanSaudi Arabia

Estrogen receptor(ER)αis expressed in a subset of patient-derived acute myeloid leukemia(AML)cells,whereas Akt is predominantly expressed in most types of *** AML with dual inhibitors is a novel approach to combat the ***,we examined a novel small molecule,3-(4-isopropyl)benzylidene-8-ethoxy,6-methyl,chroman-4-one(SBL-060),capable of targeting AML cells by inhibiting ERαand Akt *** chemical properties of SBL-060 were identified by proton nuclear magnetic resonance(^(1)H-NMR),^(13)C-NMR,and mass *** silico docking was performed using an automated protocol with ***-1 and HL-60 cell lines were differentiated using phorbol 12-myristate ***αinhibition was assessed using *** MTT assay assessed cell *** cytometry was performed for cell cycle,apoptosis,and p-Akt *** analysis identified the compound as 3-(4-isopropyl)benzylidene-8-ethoxy,6-methyl,chroman-4-one,which showed high binding efficacy toward ER,with aΔG_(binding) score of−7.4 kcal/***-060 inhibited ERα,exhibiting IC50 values of 448 and 374.3 nM in THP-1 and HL-60 cells,*** inhibited cell proliferation,GI50 values of SBL-060 were 244.1 and 189.9 nM for THP-1 and HL-60 cells,*** addition,a dose-dependent increase in sub G_(0)/G_(1) phase cell cycle arrest and total apoptosis was observed after treatment with SBL-060 in both cell ***-060 also dose-dependently increased the p-Akt-positive populations in both THP-1 and HL-60 *** results indicate that SBL-060 has excellent efficacy against differentiated AML cell types by inhibiting ER and Akt kinase,warranting further preclinical evaluations.

关键词： Akt kinase AML THP-1 HL-60 Estrogen receptor Benzylidene compounds

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