Journal
NEOPLASIA
Volume 22, Issue 12, Pages 714-724Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neo.2020.10.004
Keywords
PI3K delta; Inhibition; SHC014748M; Preclinical; Lymphoma
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Funding
- National Natural Science Foundation of China [81720108002]
- Jiangsu Provincial Special Program of Medical Science [BE2017751]
- National Science and Technology Major Project [2018ZX09734007]
- Excellent Youth Foundation Project of JiangSu Province [BK20160099, 2015-WSN-050]
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PI3K delta (phosphatidylinositol 3-kinase-delta), one of the class I PI3Ks, is found expressed primarily in leukocytes and plays an essential role in B-cell development and function. This provides a rationale for the development of small molecule inhibitors that selectively target p110 delta for patients with indolent non-Hodgkin lymphomas. Here in this paper, we comprehensively evaluated the in vitro and in vivo antitumor activity of SHC014748M, an oral selective inhibitor of PI3K delta under Phase I clinical evaluation. Biochemical and cell-based assays were used to measure compound potency and selectivity in lymphoma cell lines as well as primary chronic lymphocytic leukemia (CLL) cells. Scid mice were subcutaneously inoculated with the SU-DHL-6 cell line. SHC014748M was more selective for PI3K delta inhibition relative to other class I PI3K enzymes and showed in vitro activity in most of 23 B lymphoma cell lines and primary CLL cells. SHC014748M also inhibited phosphorylation of AKT, targets downstream of PI3K delta, in both lymphoma cells and primary CLL cells. In vivo study revealed that SHC014748M significantly reduced lymphoma cell growth in the treatment group compared with control mice. CCL4, CCL17, CCL22 and CXCL13 in patient serum decreased sharply after SHC014748M treatment. According to the results, SHC014748M appeared to be a novel promising compound in the treatment of B cell lymphomas and CLL.
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