Identification of a promising PI3K inhibitor for the treatment of multiple myeloma through the structural optimization

Abstract

BackgroundWe previously reported a PI3K inhibitor S14161 which displays a promising preclinical activity against multiple myeloma (MM) and leukemia, but the chiral structure and poor solubility prevent its further application.MethodsSix S14161 analogs were designed based on the structure–activity relationship; activity of the compounds in terms of cell death and inhibition of PI3K were analyzed by flow cytometry and Western blotting, respectively; anti-myeloma activity in vivo was performed on two independent xenograft models.ResultsAmong the six analogs, BENC-511 was one of the most potent compounds which significantly inhibited PI3K activity and induced MM cell apoptosis. BENC-511 was able to inactivate PI3K and its downstream signals AKT, mTOR, p70S6K, and 4E-BP1 at 1 μM but had no effects on their total protein expression. Consistent with its effects on PI3K activity, BENC-511 induced MM cell apoptosis which was evidenced by the cleavage of Caspase-3 and PARP. Notably, addition of insulin-like growth factor 1 and interleukin-6, two important triggers for PI3K activation in MM cells, partly blocked BENC-511-induced MM cell death, which further demonstrated that PI3K signaling pathway was critical for the anti-myeloma activity of BENC-511. Moreover, BENC-511 also showed potent oral activity against myeloma in vivo. Oral administration of BENC-511 decreased tumor growth up to 80% within 3 weeks in two independent MM xenograft models at a dose of 50 mg/kg body weight, but presented minimal toxicity. Suppression of BENC-511 on MM tumor growth was associated with decreased PI3K/AKT activity and increased cell apoptosis.ConclusionsBecause of its potent anti-MM activity, low toxicity (LD50 oral >1.5 g/kg), and easy synthesis, BENC-511 could be developed as a promising agent for the treatment of MM via suppressing the PI3K/AKT signaling pathway.

MicroRNA‐26a inhibits multiple myeloma cell growth by suppressing cyclin‐dependent kinase 6 expression

“…Whole cell lysates were prepared for immunoblotting as described previously . Equal amounts of total proteins (30 μg) were subjected to SDS‐PAGE separation, followed by immunoblotting analysis with specific antibodies.…”

Identification specific miRNA in t(4;14) multiple myeloma based on miRNA‐mRNA expressing profile correlation analysis

“…There were four genes enriched in focal adhesion pathway, such as CCND2, IGF1R, LAMC1, and TLN2. Previous studies have reported that the dysregulation of PI3K‐Akt signaling pathway was closely related to MM and may be the potential therapeutic target for MM in the future . In addition, CCND2 had been reported many times in reducing apoptosis of MM cells .…”

Investigation of ErbB and Insulin Signaling Pathways in the Pathogenesis of Multiple Myeloma

“…PI3K / AKT signaling pathway is important for MM cell proliferation, survival and anti-apoptosis. Reduced activation of PI3K gene leads to MM cell death but increased activation of PI3K gene lead to proliferation (16). Study of Azabu and et al (17) in 2013, they detected increased expression of genes in PI3KCA.…”