ZIYU LIU^1,2, AKIKO OKANO^3,4, EMIKO SANADA^1,3,4, YUSHI FUTAMURA^3,4, TOSHIHIKO NOGAWA^3,5, KOSUKE ISHIKAWA⁶, KENTARO SEMBA^7,8, JIANG LI⁹, XIAOMENG LI¹⁰, HIROYUKI OSADA^3,4,11,*, NOBUMOTO WATANABE^1,2,4,*

Oncology Research, Vol.31, No.5, pp. 655-666, 2023, DOI:10.32604/or.2023.030248

Abstract

Myc belongs to a family of proto-oncogenes that encode transcription factors. The overexpression of c-Myc causes many types of cancers. Recently, we established a system for screening c-Myc inhibitors and identified antimycin A by screening the RIKEN NPDepo chemical library. The specific mechanism of promoting tumor cell metastasis by high c-Myc expression remains to be explained. In this study, we screened approximately 5,600 microbial extracts using this system and identified a broth prepared from Streptomyces sp. RK19-A0402 strongly inhibits c-Myc transcriptional activity. After purification of the hit broth, we identified compounds closely related to the aglycone of cytovaricin and had… More > Graphic Abstract

XINTONG LIU^1,2,3, EMIKO SANADA^1,3,4, JIANG LI⁵, XIAOMENG LI⁶, HIROYUKI OSADA^1,4,7,*, NOBUMOTO WATANABE^1,2,3,*

Oncology Research, Vol.31, No.5, pp. 645-654, 2023, DOI:10.32604/or.2023.030240

Abstract β-transducin repeat-containing protein (β-TrCP) is an F-box protein subunit of the E3 Skp1-Cullin-F box (SCF) type ubiquitin-ligase complex, and provides the substrate specificity for the ligase. To find potent ligands of β-TrCP useful for the proteolysis targeting chimera (PROTAC) system using β-TrCP in the future, we developed a high-throughput screening system for small molecule β-TrCP ligands. We screened the chemical library utilizing the system and obtained several hit compounds. The effects of the hit compounds on in vitro ubiquitination activity of SCF^β-TrCP1 and on downstream signaling pathways were examined. Hit compounds NPD5943, NPL62020-01, and NPL42040-01 inhibited the TNFα-induced degradation of… More > Graphic Abstract

FAISAL HASSAN TOBEIGEI¹, REEM M. GAHTANI², AHMAD SHAIKH², AMER AL ALI³, NADER KAMELI^4,5, HOSSAM KAMLI², PRASANNA RAJAGOPALAN^2,6,*

Oncology Research, Vol.29, No.5, pp. 305-318, 2021, DOI:10.32604/or.2022.025187

Abstract Malignant melanoma is characterized by both genetic and molecular alterations that activate phosphoinositide 3-kinase (PI3K), and RAS/BRAF pathways. In this work, through diversity-based high-throughput virtual screening we identified a lead molecule that selectively targets PI3K and BRAF^V600E kinases. Computational screening, Molecular dynamics simulation and MMPBSA calculations were performed. PI3K 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 analysis. Computational screening of small molecules indicates compound CB-006-3 selectively targets PI3KCG (gamma subunit), PI3KCD (delta subunit) and BRAF^V600E. Molecular dynamics simulation… More >