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Quassinoid analogs with enhanced efficacy for treatment of hematologic malignancies specifically target the PI3Kgamma isoform

ABSTRACT: Development of novel PI3Ks inhibitors is an important strategy to overcome their resistance and poor tolerability in clinical trials. The quassinoid family member Brusatol shows specific inhibitory activity against hematologic malignancies. However, the mechanism of its anti-cancer activity is unknown. We studied the anti-cancer activity of Brusatol on multiple hematologic malignancies derived cell lines by RNA-Seq, mass spectrometry, biochemical pull-down assays, and CRISPR/Cas9 gene knock-out. We demonstrated that the PI3Kgamma isoform was identified as a direct target of Brusatol, and inhibition was lost on PI3Kgamma deficient cells. Novel synthetic analogs were also developed and tested in vitro and in vivo. They shared superior potency in their ability to inhibit malignant hematologic cell lines, and in a xenograft transplant mouse model. They also had minimal toxicity to normal human cells. These new analogs have enhanced potential for development as a new class of PI3K inhibitors for treatment of hematologic malignancies.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Erle Robertson

PROVIDER: MSV000085067 | MassIVE | Fri Mar 06 10:04:00 GMT 2020

REPOSITORIES: MassIVE

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Quassinoid analogs with enhanced efficacy for treatment of hematologic malignancies specifically target the PI3Kgamma isoform

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