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SHC014748M, a novel selective inhi-bitor of PI3K?, demonstrates promising preclinical antitumor activity in B cell lymphomas and chronic lymphocytic leukemia.

ABSTRACT: PI3K? (phosphatidylinositol 3-kinase-?), 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? 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? 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? 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?, 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.

SUBMITTER: Fan L

PROVIDER: S-EPMC7586065 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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SHC014748M, a novel selective inhi-bitor of PI3Kδ, demonstrates promising preclinical antitumor activity in B cell lymphomas and chronic lymphocytic leukemia.

Fan Lei L Wang Chao C Zhao Liwen L Wang Zhiqiang Z Zhang Xian X Liu Xiaorong X Cao Lei L Xu Wei W Li Jianyong J

Neoplasia (New York, N.Y.) 20201023 12

PI3Kδ (phosphatidylinositol 3-kinase-δ), 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 p110δ 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 PI3Kδ under Phase I clinical eva ...[more]

PMID: 33142237

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Project description:Previous studies have shown increased familial risk for chronic lymphocytic leukemia. In the most comprehensive study to date, we evaluated risk of chronic lymphocytic leukemia and lymphoproliferative disorders among first-degree relatives of chronic lymphocytic leukemia cases compared to first-degree relatives of controls.Population-based registry data from Sweden were used to evaluate outcomes in 26,947 first-degree relatives of 9,717 chronic lymphocytic leukemia patients (diagnosed 1958-2004) compared with 107,223 first-degree relatives of 38,159 matched controls. Using a marginal survival model, we calculated relative risks (RR) and 95% confidence intervals as measures of familial aggregation.Compared to relatives of controls, relatives of chronic lymphocytic leukemia patients had an increased risk for chronic lymphocytic leukemia (RR=8.5, 6.1-11.7) and other non-Hodgkin's lymphomas (NHLs) (RR=1.9, 1.5-2.3). Evaluating NHL subtypes, we found a striking excess of indolent B-cell NHL, specifically lymphoplasmacytic lymphoma/Waldenström macroglobulinemia and hairy cell leukemia. No excesses of aggressive B-cell or T-cell lymphomas were found. There was no statistical excess of Hodgkin's lymphoma, multiple myeloma, or the precursor condition, monoclonal gammopathy of undetermined significance, among chronic lymphocytic leukemia relatives.These familial aggregations are striking and provide novel clues to research designed to uncover early pathogenetic mechanisms in chronic lymphocytic leukemia including studies to identify germ line susceptibility genes. However, clinicians should counsel their chronic lymphocytic leukemia patients emphasizing that because the baseline population risks are low, the absolute risk for a first-degree relative to develop chronic lymphocytic leukemia or another indolent lymphoma is low. At this time, an increased medical surveillance of first-degree relatives of chronic lymphocytic leukemia patients has no role outside research studies.

Dataset Information

SHC014748M, a novel selective inhi-bitor of PI3K?, demonstrates promising preclinical antitumor activity in B cell lymphomas and chronic lymphocytic leukemia.

Publications

SHC014748M, a novel selective inhi-bitor of PI3Kδ, demonstrates promising preclinical antitumor activity in B cell lymphomas and chronic lymphocytic leukemia.

Similar Datasets

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