{"doi":"10.3389/fonc.2021.766888","title":"Preclinical Evaluation of a Novel Dual Targeting PI3Kδ/BRD4 Inhibitor, SF2535, in B-Cell Acute Lymphoblastic Leukemia","abstract":"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 using in 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.","journal":"Frontiers in Oncology","year":2021,"id":210104,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":249837,"name":"Hye Na Kim","orcid":"0000-0003-0953-2372","position":1,"is_corresponding":false},{"id":257944,"name":"Heather Ogana","orcid":"0000-0002-1541-3698","position":2,"is_corresponding":false},{"id":582906,"name":"Zesheng Wan","orcid":null,"position":3,"is_corresponding":false},{"id":798197,"name":"Samantha Hurwitz","orcid":"0000-0002-6580-3379","position":4,"is_corresponding":false},{"id":792839,"name":"Cydney Nichols","orcid":"0000-0003-4024-5339","position":5,"is_corresponding":false},{"id":260932,"name":"Nour Abdel‐Azim","orcid":null,"position":6,"is_corresponding":false},{"id":798688,"name":"Ariana Coba","orcid":null,"position":7,"is_corresponding":false},{"id":798689,"name":"Seyoung Seo","orcid":null,"position":8,"is_corresponding":false},{"id":328294,"name":"Yong‐Hwee Eddie Loh","orcid":"0000-0002-6185-9279","position":9,"is_corresponding":false},{"id":257946,"name":"Eun Ji Gang","orcid":"0000-0002-7475-2059","position":10,"is_corresponding":false},{"id":249842,"name":"Hisham Abdel‐Azim","orcid":"0000-0003-0880-8701","position":11,"is_corresponding":false},{"id":402306,"name":"Chih‐Lin Hsieh","orcid":"0000-0003-2082-5053","position":12,"is_corresponding":false},{"id":402307,"name":"Michael R. Lieber","orcid":"0000-0003-3700-6345","position":13,"is_corresponding":false},{"id":321465,"name":"Chintan Parekh","orcid":"0000-0001-8100-9151","position":14,"is_corresponding":false},{"id":416601,"name":"Dhananjaya Pal","orcid":"0000-0001-7675-4819","position":15,"is_corresponding":false},{"id":262386,"name":"Deepa Bhojwani","orcid":"0000-0002-7559-7927","position":16,"is_corresponding":false},{"id":267282,"name":"Donald L. 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