Preclinical Evaluation of a Novel Dual Targeting PI3Kδ/BRD4 Inhibitor, SF2535, in B-Cell Acute Lymphoblastic Leukemia.
Preclinical Evaluation of a Novel Dual Targeting PI3Kδ/BRD4 Inhibitor, SF2535, in B-Cell Acute Lymphoblastic Leukemia.
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DOI：
10.3389/fonc.2021.766888
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发表时间：
2021
影响因子：
4.7
通讯作者：
Kim YM
中科院分区：
文献类型：
--
作者：
Ruan Y;Kim HN;Ogana HA;Wan Z;Hurwitz S;Nichols C;Abdel-Azim N;Coba A;Seo S;Loh YE;Gang EJ;Abdel-Azim H;Hsieh CL;Lieber MR;Parekh C;Pal D;Bhojwani D;Durden DL;Kim YM
已知PI 3 K/Akt通路-特别是PI 3 K δ-在耐药B细胞急性淋巴细胞白血病（B-ALL）中的作用，并且其通常在难治性或复发性B-ALL中上调。Myc蛋白是负责转录促增殖基因的转录因子，并且c-Myc通常在癌症中过表达。染色质调节因子BRD 4是恶性血液病（包括B-ALL）中c-Myc表达所必需的。先前，BRD 4和PI 3 K抑制与SF 2523的组合显示成功地降低Myc表达。然而，PI 3 K δ/BRD 4双重抑制在B-ALL中的潜在机制和作用仍然未知。为了研究这一点，我们利用了SF 2535，一种新型的小分子双重抑制剂，可以特异性靶向PI 3 K δ亚型和BRD 4。我们用不同浓度的SF 2535处理原代B-ALL细胞，并使用体外和体内模型研究其对特定药理学靶向机制如凋亡、细胞周期、细胞增殖和粘附分子表达的影响。SF 2535通过抑制c-Myc启动子位点的BRD 4显著下调c-Myc mRNA和蛋白表达，并通过抑制PI 3 K δ/AKT通路降低p-AKT表达。SF 2535通过下调BCL-2和增加caspase-3、caspase-7和PARP的裂解诱导B-ALL细胞凋亡。此外，SF 2535诱导B-ALL细胞周期阻滞和细胞计数减少。有趣的是，SF 2535降低了整合素α4、α5、α6和β1的平均荧光强度（MFI），同时增加了CXCR 4的MFI，表明SF 2535可能通过整合素的由内而外信号传导起作用。总之，我们的数据为使用SF 2535靶向PI 3 K δ/BRD 4治疗难治性或复发性B-ALL的临床评价提供了依据。
The PI3K/Akt pathway—and in particular PI3Kδ—is known for its role in drug resistant B-cell acute lymphoblastic leukemia (B-ALL) and it is often upregulated in refractory or relapsed B-ALL. Myc proteins are transcription factors responsible for transcribing pro-proliferative genes and c-Myc is often overexpressed in cancers. The chromatin regulator BRD4 is required for expression of c-Myc in hematologic malignancies including B-ALL. Previously, combination of BRD4 and PI3K inhibition with SF2523 was shown to successfully decrease Myc expression. However, the underlying mechanism and effect of dual inhibition of PI3Kδ/BRD4 in B-ALL remains unknown. To study this, we utilized SF2535, a novel small molecule dual inhibitor which can specifically target the PI3Kδ isoform and BRD4. We treated primary B-ALL cells with various concentrations of SF2535 and studied its effect on specific pharmacological on-target mechanisms such as apoptosis, cell cycle, cell proliferation, and adhesion molecules expression usingin vitro and in vivo models. SF2535 significantly downregulates both c-Myc mRNA and protein expression through inhibition of BRD4 at the c-Myc promoter site and decreases p-AKT expression through inhibition of the PI3Kδ/AKT pathway. SF2535 induced apoptosis in B-ALL by downregulation of BCL-2 and increased cleavage of caspase-3, caspase-7, and PARP. Moreover, SF2535 induced cell cycle arrest and decreased cell counts in B-ALL. Interestingly, SF2535 decreased the mean fluorescence intensity (MFI) of integrin α4, α5, α6, and β1 while increasing MFI of CXCR4, indicating that SF2535 may work through inside-out signaling of integrins. Taken together, our data provide a rationale for the clinical evaluation of targeting PI3Kδ/BRD4 in refractory or relapsed B-ALL using SF2535.
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BET抑制作用是原发性B-培训急性淋巴细胞白血病的单一或联合治疗方法。
影响因子：
12.8
作者：
Da Costa, D.;Agathanggelou, A.;Perry, T.;Weston, V.;Petermann, E.;Zlatanou, A.;Oldreive, C.;Wei, W.;Stewart, G.;Longman, J.;Smith, E.;Kearns, P.;Knapp, S.;Stankovic, T.
通讯作者：
Stankovic, T.
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
5.2
作者：
Adam, Etai;Kim, Hye Na;Kim, Yong-Mi
通讯作者：
Kim, Yong-Mi
影响因子：
20.3
作者：
Gang, Eun Ji;Kim, Hye Na;Kim, Yong-Mi
通讯作者：
Kim, Yong-Mi
影响因子：
8
作者：
Boudjadi S;Carrier JC;Groulx JF;Beaulieu JF
通讯作者：
Beaulieu JF