Characterization of selective and potent PI3Kd inhibitor (PI3KDIN-015) for B-Cell malignances

Xiaochuan Liu; Aoli Wang; Xiaofei Liang; Cheng Chen; Juanjuan Liu; Zheng Zhao; Hong Wu; Yuanxin Deng; Li Wang; Beilei Wang; Jiaxin Wu; Feiyang Liu; Stacey M. Fernandes; Sophia Adamia; Richard M. Stone; Ilene A. Galinsky; Jennifer R. Brown; James D. Griffin; Shanchun Zhang; Teckpeng Loh; Xin Zhang; Wenchao Wang; Ellen L. Weisberg; Jing Liu; Qingsong Liu

doi:10.18632/oncotarget.8702

Characterization of selective and potent PI3Kd inhibitor (PI3KDIN-015) for B-Cell malignances

Xiaochuan Liu, Aoli Wang, Xiaofei Liang, Cheng Chen, Juanjuan Liu, Zheng Zhao, Hong Wu, Yuanxin Deng, Li Wang, Beilei Wang, Jiaxin Wu, Feiyang Liu, Stacey M. Fernandes, Sophia Adamia, Richard M. Stone, Ilene A. Galinsky, Jennifer R. Brown, James D. Griffin, Shanchun Zhang, Teckpeng LohXin Zhang, Wenchao Wang, Ellen L. Weisberg, Jing Liu, Qingsong Liu

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

PI3Kd is predominately expressed in leukocytes and has been found overexpressed in B-cell related malignances such as CLL and AML. We have discovered a highly selective ATP competitive PI3Kd inhibitor PI3KD-IN-015, which exhibits a high selectivity among other PI3K isoforms in both biochemical assays and cellular assay, meanwhile did not inhibit most of other protein kinases in the kinome. PI3KDIN- 015 demonstrates moderately anti-proliferation efficacies against a variety of B-cell related cancer cell lines through down-regulate the PI3K signaling significantly. It induced both apoptosis and autophagy in B-cell malignant cell lines. In addition, combination of autophagy inhibitor Bafilomycin could potentiate the moderate antiproliferation effect of PI3KD-IN-015. PI3KD-IN-015 shows anti-proliferation efficacy against CLL and AML patient primary cells. Collectively, these results indicate that PI3KD-IN-015 may be useful drug candidate for further development of anti-B-cell related malignances therapies.

Original language	English
Pages (from-to)	32641-32651
Number of pages	11
Journal	Oncotarget
Volume	7
Issue number	22
DOIs	https://doi.org/10.18632/oncotarget.8702
State	Published - 31 May 2016
Externally published	Yes

Keywords

B-cell malignances
Kinase inhibitors
Leukemia
PI3K
PI3Kd

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.18632/oncotarget.8702

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Liu, X., Wang, A., Liang, X., Chen, C., Liu, J., Zhao, Z., Wu, H., Deng, Y., Wang, L., Wang, B., Wu, J., Liu, F., Fernandes, S. M., Adamia, S., Stone, R. M., Galinsky, I. A., Brown, J. R., Griffin, J. D., Zhang, S., ... Liu, Q. (2016). Characterization of selective and potent PI3Kd inhibitor (PI3KDIN-015) for B-Cell malignances. Oncotarget, 7(22), 32641-32651. https://doi.org/10.18632/oncotarget.8702

@article{25e0a0fdeafe4bbb99e2c95f4ffb65d5,

title = "Characterization of selective and potent PI3Kd inhibitor (PI3KDIN-015) for B-Cell malignances",

abstract = "PI3Kd is predominately expressed in leukocytes and has been found overexpressed in B-cell related malignances such as CLL and AML. We have discovered a highly selective ATP competitive PI3Kd inhibitor PI3KD-IN-015, which exhibits a high selectivity among other PI3K isoforms in both biochemical assays and cellular assay, meanwhile did not inhibit most of other protein kinases in the kinome. PI3KDIN- 015 demonstrates moderately anti-proliferation efficacies against a variety of B-cell related cancer cell lines through down-regulate the PI3K signaling significantly. It induced both apoptosis and autophagy in B-cell malignant cell lines. In addition, combination of autophagy inhibitor Bafilomycin could potentiate the moderate antiproliferation effect of PI3KD-IN-015. PI3KD-IN-015 shows anti-proliferation efficacy against CLL and AML patient primary cells. Collectively, these results indicate that PI3KD-IN-015 may be useful drug candidate for further development of anti-B-cell related malignances therapies.",

keywords = "B-cell malignances, Kinase inhibitors, Leukemia, PI3K, PI3Kd",

author = "Xiaochuan Liu and Aoli Wang and Xiaofei Liang and Cheng Chen and Juanjuan Liu and Zheng Zhao and Hong Wu and Yuanxin Deng and Li Wang and Beilei Wang and Jiaxin Wu and Feiyang Liu and Fernandes, {Stacey M.} and Sophia Adamia and Stone, {Richard M.} and Galinsky, {Ilene A.} and Brown, {Jennifer R.} and Griffin, {James D.} and Shanchun Zhang and Teckpeng Loh and Xin Zhang and Wenchao Wang and Weisberg, {Ellen L.} and Jing Liu and Qingsong Liu",

year = "2016",

month = may,

day = "31",

doi = "10.18632/oncotarget.8702",

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Liu, X, Wang, A, Liang, X, Chen, C, Liu, J, Zhao, Z, Wu, H, Deng, Y, Wang, L, Wang, B, Wu, J, Liu, F, Fernandes, SM, Adamia, S, Stone, RM, Galinsky, IA, Brown, JR, Griffin, JD, Zhang, S, Loh, T, Zhang, X, Wang, W, Weisberg, EL, Liu, J & Liu, Q 2016, 'Characterization of selective and potent PI3Kd inhibitor (PI3KDIN-015) for B-Cell malignances', Oncotarget, vol. 7, no. 22, pp. 32641-32651. https://doi.org/10.18632/oncotarget.8702

TY - JOUR

T1 - Characterization of selective and potent PI3Kd inhibitor (PI3KDIN-015) for B-Cell malignances

AU - Liu, Xiaochuan

AU - Wang, Aoli

AU - Liang, Xiaofei

AU - Chen, Cheng

AU - Liu, Juanjuan

AU - Zhao, Zheng

AU - Wu, Hong

AU - Deng, Yuanxin

AU - Wang, Li

AU - Wang, Beilei

AU - Wu, Jiaxin

AU - Liu, Feiyang

AU - Fernandes, Stacey M.

AU - Adamia, Sophia

AU - Stone, Richard M.

AU - Galinsky, Ilene A.

AU - Brown, Jennifer R.

AU - Griffin, James D.

AU - Zhang, Shanchun

AU - Loh, Teckpeng

AU - Zhang, Xin

AU - Wang, Wenchao

AU - Weisberg, Ellen L.

AU - Liu, Jing

AU - Liu, Qingsong

PY - 2016/5/31

Y1 - 2016/5/31

N2 - PI3Kd is predominately expressed in leukocytes and has been found overexpressed in B-cell related malignances such as CLL and AML. We have discovered a highly selective ATP competitive PI3Kd inhibitor PI3KD-IN-015, which exhibits a high selectivity among other PI3K isoforms in both biochemical assays and cellular assay, meanwhile did not inhibit most of other protein kinases in the kinome. PI3KDIN- 015 demonstrates moderately anti-proliferation efficacies against a variety of B-cell related cancer cell lines through down-regulate the PI3K signaling significantly. It induced both apoptosis and autophagy in B-cell malignant cell lines. In addition, combination of autophagy inhibitor Bafilomycin could potentiate the moderate antiproliferation effect of PI3KD-IN-015. PI3KD-IN-015 shows anti-proliferation efficacy against CLL and AML patient primary cells. Collectively, these results indicate that PI3KD-IN-015 may be useful drug candidate for further development of anti-B-cell related malignances therapies.

AB - PI3Kd is predominately expressed in leukocytes and has been found overexpressed in B-cell related malignances such as CLL and AML. We have discovered a highly selective ATP competitive PI3Kd inhibitor PI3KD-IN-015, which exhibits a high selectivity among other PI3K isoforms in both biochemical assays and cellular assay, meanwhile did not inhibit most of other protein kinases in the kinome. PI3KDIN- 015 demonstrates moderately anti-proliferation efficacies against a variety of B-cell related cancer cell lines through down-regulate the PI3K signaling significantly. It induced both apoptosis and autophagy in B-cell malignant cell lines. In addition, combination of autophagy inhibitor Bafilomycin could potentiate the moderate antiproliferation effect of PI3KD-IN-015. PI3KD-IN-015 shows anti-proliferation efficacy against CLL and AML patient primary cells. Collectively, these results indicate that PI3KD-IN-015 may be useful drug candidate for further development of anti-B-cell related malignances therapies.

KW - B-cell malignances

KW - Kinase inhibitors

KW - Leukemia

KW - PI3K

KW - PI3Kd

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U2 - 10.18632/oncotarget.8702

DO - 10.18632/oncotarget.8702

M3 - 文章

C2 - 27081697

AN - SCOPUS:84973532015

SN - 1949-2553

VL - 7

SP - 32641

EP - 32651

JO - Oncotarget

JF - Oncotarget

IS - 22

ER -

Characterization of selective and potent PI3Kd inhibitor (PI3KDIN-015) for B-Cell malignances

Abstract

Keywords

UN SDGs

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