Elsevier

Neoplasia

Volume 22, Issue 12, December 2020, Pages 714-724
Neoplasia

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

https://doi.org/10.1016/j.neo.2020.10.004Get rights and content
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open access

Highlights

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    SHC014748M was proved to be more selective for PI3Kδ inhibition relative to other class i PI3K enzymes.

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    SHC014748M showed in vitro activity in most of 23 B lymphoma cell lines and primary CLL cells and also inhibited phosphorylation of AKT, targets downstream of PI3Kδ.

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    In vivo study revealed that SHC014748M significantly reduced lymphoma cell growth in the treatment group compared with control mice.

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    SHC014748M seemed to be a novel promising compound in the treatment of B cell lymphomas and CLL.

Abstract

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 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 PI3Kδ 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 PI3Kδ, 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.

Keywords

PI3Kδ
Inhibition
SHC014748M
Preclinical
Lymphoma

Abbreviations

7-AAD
7-Aminoactinomycin D
ADR
adverse drug reactions
ANOVA
analysis of variance
BCRs
b-cell antigen receptors
BCA
bicinchoninic acid
CIT
chemoimmunotherapy
FBS
fetal bovine serum
FL
follicular lymphoma
iNHL
indolent non-Hodgkin lymphomas
CLL/SLL
lymphocytic lymphoma
mTOR
mammalian target of rapamycin
NHL
non-Hodgkin lymphomas
PI3Ks
phosphatidylinositol 3-kinase
RIT
radioimmunotherapy
SDS
sodium dodecyl sulfate
STS
staurosporine
IC50
the 50% inhibitory concentration
WM/LPL
Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma

Cited by (0)

Funding: This work was supported by National Natural Science Foundation of China (81720108002); Jiangsu Provincial Special Program of Medical Science (BE2017751), and National Science and Technology Major Project (2018ZX09734007); Excellent Youth Foundation Project of JiangSu Province (BK20160099); “Liu Da Ren Cai Gao Feng” of JiangSu Province (2015-WSN-050).

Declaration of Competing Interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

1

Lei Fan and Chao Wang contributed equally to this work.

© 2020 The Authors. Published by Elsevier Inc.