A Novel Triple-Action Inhibitor Targeting B-Cell Receptor Signaling and BRD4 Demonstrates Preclinical Activity in Chronic Lymphocytic Leukemia

Smith, Audrey L.; Eiken, Alexandria P.; Skupa, Sydney A.; Moore, Dalia; Umeta, Lelisse T.; Smith, Lynette M.; Lyden, Elizabeth; D'Angelo, Christopher; Kallam, Avyakta; Vose, Julie M.; Kutateladze, Tatiana G.; El‐Gamal, Dalia

doi:10.3390/ijms23126712

Cited by 9 publications

(14 citation statements)

References 85 publications

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“…Since SpiD3 sensitized CLL cells to ibrutinib, we sought to assess the effects of SpiD3 in ibrutinib-resistant HG-3 (IR-HG3) cells. Consistent with reported studies [17], the anti-proliferative effects of ibrutinib were attenuated in IR-HG3 cells. Remarkably, SpiD3 exhibited robust anti-proliferative effects in IR-HG3 cells with comparable IC 50 to parental wild-type HG-3 (WT-HG3) cells (Fig.…”

Section: Resultssupporting

confidence: 92%

“…Malignant B-cell lines (20-80,000 cells/well; 72 h), patient-derived CLL samples (0.7e 6 cells/well; 48 h ± CpG), murine Eμ-Myc/TCL1 or Eμ-TCL1 lymphocytes (0.6e 6 cells/well; 48 h ± PMA/Ionomycin) were treated with vehicle (DMSO) or increasing inhibitor concentrations (single or combined). Cell proliferation was evaluated using CellTiter 96® Aqueous MTS assay (Promega; Madison, WI) as previously described [17]. GraphPad Prism v9.4.1 (GraphPad Software, Inc.; San Diego, CA) was used to calculate the half-maximal inhibitory concentration (IC 50 ).…”

Section: Methodsmentioning

confidence: 99%

“…OSU-CLL cells [16] were provided by the Human Genetics Sample Bank of The Ohio State University (Columbus, OH). Ibrutinib-resistant HG-3 cells were generated by prolonged exposure to increasing concentrations of ibrutinib [17]. HG-3, RI-1, OSU-CLL, MEC1, MEC2, DB, SUDHL6, RC, Jeko-1, and 9-15c cell lines were cultured in RPMI-1640 with 2 mM L-glutamine (Sigma-Aldrich; St. Louis, MO), supplemented with 100 U/mL penicillin/100 μg/mL streptomycin (P/S, Sigma-Aldrich), and 10% heat-inactivated fetal bovine serum (hi-FBS, Avantor®; Radnor, PA).…”

Section: Cell Lines and Primary Cll Cell Processingmentioning

confidence: 99%

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Novel spirocyclic dimer, SpiD3, targets chronic lymphocytic leukemia survival pathways with potent preclinical effects

Eiken,

Smith,

Skupa

et al. 2024

Preprint

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Chronic lymphocytic leukemia (CLL) cell survival and growth is fueled by the induction of B-cell receptor (BCR) signaling within the tumor microenvironment (TME) driving activation of NF- κB signaling and the unfolded protein response (UPR). Malignant cells have higher basal levels of UPR posing a unique therapeutic window to combat CLL cell growth using pharmacological agents that induce accumulation of misfolded proteins. Frontline CLL therapeutics that directly target BCR signaling such as Bruton-tyrosine kinase (BTK) inhibitors (e.g., ibrutinib) have enhanced patient survival. However, resistance mechanisms wherein tumor cells bypass BTK inhibition through acquired BTK mutations, and/or activation of alternative survival mechanisms have rendered ibrutinib ineffective, imposing the need for novel therapeutics. We evaluated SpiD3, a novel spirocyclic dimer, in CLL cell lines, patient-derived CLL samples, ibrutinib-resistant CLL cells, and in the Eµ-TCL1 mouse model. Our integrated multi-omics and functional analyses revealed BCR signaling, NF-κB signaling, and endoplasmic reticulum stress among the top pathways modulated by SpiD3. This was accompanied by marked upregulation of the UPR and inhibition of global protein synthesis in CLL cell lines and patient-derived CLL cells. In ibrutinib-resistant CLL cells, SpiD3 retained its anti-leukemic effects, mirrored in reduced activation of key proliferative pathways (e.g., PRAS, ERK, MYC). Translationally, we observed reduced tumor burden in SpiD3-treated Eµ-TCL1 mice. Our findings reveal that SpiD3 exploits critical vulnerabilities in CLL cells including NF-κB signaling and the UPR, culminating in profound anti-tumor properties independent of TME stimuli.STATEMENT OF SIGNIFICANCESpiD3 demonstrates cytotoxicity in CLL partially through inhibition of NF-κB signaling independent of tumor-supportive stimuli. By inducing the accumulation of unfolded proteins, SpiD3 activates the UPR and hinders protein synthesis in CLL cells. Overall, SpiD3 exploits critical CLL vulnerabilities (i.e., the NF-κB pathway and UPR) highlighting its use in drug-resistant CLL.VISUAL ABSTRACT

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Section: Resultssupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Cell Lines and Primary Cll Cell Processingmentioning

confidence: 99%

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Novel spirocyclic dimer, SpiD3, targets chronic lymphocytic leukemia survival pathways with potent preclinical effects

Eiken,

Smith,

Skupa

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

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“…Thanks to the success of these drugs, novel combinations are making their way into the therapeutic scenario of CLL. To name a few of the recent discoveries in targeting CLL cells, SRX3305, a novel small-molecule that targets BTK/PI3K/BRD4 in CLL cells, disrupts CLL cell proliferation and promotes apoptosis [ 9 ]. The multi-kinase inhibitor TG02 inhibits cyclin-dependent kinase 9 blocking the activation of RNA polymerase II, thus leading to Mcl-1 depletion and, to rapid apoptosis [ 10 ].…”

Section: State Of the Art Of Treatment In Onco-hematological Diseasesmentioning

confidence: 99%

Is It Still Possible to Think about HSP70 as a Therapeutic Target in Onco-Hematological Diseases?

et al. 2023

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The search for molecules to be targeted that are involved in apoptosis resistance/increased survival and pathogenesis of onco-hematological malignancies is ongoing since these diseases are still not completely understood. Over the years, a good candidate has been identified in the Heat Shock Protein of 70kDa (HSP70), a molecule defined as “the most cytoprotective protein ever been described”. HSP70 is induced in response to a wide variety of physiological and environmental insults, allowing cells to survive lethal conditions. This molecular chaperone has been detected and studied in almost all the onco-hematological diseases and is also correlated to poor prognosis and resistance to therapy. In this review, we give an overview of the discoveries that have led us to consider HSP70 as a therapeutic target for mono- or combination-therapies in acute and chronic leukemias, multiple myeloma and different types of lymphomas. In this excursus, we will also consider HSP70 partners, such as its transcription factor HSF1 or its co-chaperones whose druggability could indirectly affect HSP70. Finally, we will try to answer the question asked in the title of this review considering that, despite the effort made by research in this field, HSP70 inhibitors never reached the clinic.

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“…A Phase III study is comparing the efficacy and the safety of the first in-class selective inhibitor of nuclear export, selinexor, in combination with bortezomib + dexamethasone vs. bortezomib + dexamethasone in patients with R/R MM (NCT03110562) [ 465 ]. Pharmacological inhibition of the bromodomain and extra-terminal (BRD/BET) family proteins block downstream components of BCR signaling, downregulate Bcl-2 transcription, and suppress NF-κB signaling in CLL and B-NHL [ 466 ]; among novel single-molecules cotargeting BRD4 and other tumor targets recently developed, SRX3177 targeting CDK4/6-PI3K-BRD4 and SRX3305 targeting BTK-PI3K-BRD4, demonstrate preclinical activity against MCL [ 467 ], CLL [ 468 ], and MCL [ 469 ]. These studies underscore the potential effectiveness of these novel multi-action small molecule inhibitors, alone or combined, for potential treatment of B tumors.…”

Section: Concluding Remarks and Perspectivesmentioning

confidence: 99%

Current Status of Novel Agents for the Treatment of B Cell Malignancies: What’s Coming Next?

Tannoury

Garnier

Susin

et al. 2022

Cancers

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Resistance to death is one of the hallmarks of human B cell malignancies and often contributes to the lack of a lasting response to today’s commonly used treatments. Drug discovery approaches designed to activate the death machinery have generated a large number of inhibitors of anti-apoptotic proteins from the B-cell lymphoma/leukemia 2 family and the B-cell receptor (BCR) signaling pathway. Orally administered small-molecule inhibitors of Bcl-2 protein and BCR partners (e.g., Bruton’s tyrosine kinase and phosphatidylinositol-3 kinase) have already been included (as monotherapies or combination therapies) in the standard of care for selected B cell malignancies. Agonistic monoclonal antibodies and their derivatives (antibody–drug conjugates, antibody–radioisotope conjugates, bispecific T cell engagers, and chimeric antigen receptor-modified T cells) targeting tumor-associated antigens (TAAs, such as CD19, CD20, CD22, and CD38) are indicated for treatment (as monotherapies or combination therapies) of patients with B cell tumors. However, given that some patients are either refractory to current therapies or relapse after treatment, novel therapeutic strategies are needed. Here, we review current strategies for managing B cell malignancies, with a focus on the ongoing clinical development of more effective, selective drugs targeting these molecules, as well as other TAAs and signaling proteins. The observed impact of metabolic reprogramming on B cell pathophysiology highlights the promise of targeting metabolic checkpoints in the treatment of these disorders.

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A Novel Triple-Action Inhibitor Targeting B-Cell Receptor Signaling and BRD4 Demonstrates Preclinical Activity in Chronic Lymphocytic Leukemia

Cited by 9 publications

References 85 publications

Novel spirocyclic dimer, SpiD3, targets chronic lymphocytic leukemia survival pathways with potent preclinical effects

Novel spirocyclic dimer, SpiD3, targets chronic lymphocytic leukemia survival pathways with potent preclinical effects

Is It Still Possible to Think about HSP70 as a Therapeutic Target in Onco-Hematological Diseases?

Current Status of Novel Agents for the Treatment of B Cell Malignancies: What’s Coming Next?

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