Chemically stable inhibitors of 14-3-3 protein–protein interactions derived from BV02

Iralde-Lorente, Leire; Cau, Ylenia; Clementi, Letizia; Franci, Lorenzo; Tassone, Giusy; Valensin, Daniela; Mori, Mattia; Angelucci, Adriano; Chiariello, Mario; Botta, Maurizio

doi:10.1080/14756366.2019.1574779

Cited by 17 publications

(10 citation statements)

References 22 publications

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“…Our investigation demonstrates the underlying mechanism of hsa-miR-28-5p in the initiation and development of DLBCL. BV02 is a nonpeptide inhibitor of the 14-3-3/c-Abl protein-protein interaction, its bioactive form is phthalimide derivative 9, and inhibitors of 14-3-3 protein-protein interaction derived from BV02 are chemically stable [ 28 ]. Inosine monophosphate (IMP), pyridoxal phosphate (PLP), and the derivatives show inhibitory action of the 14-3-3/c-Abl PPI poorly [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

hsa-MicroRNA-28-5p Inhibits Diffuse Large B-Cell Lymphoma Cell Proliferation by Downregulating 14-3-3ζ Expression

Yan

Chen

Yang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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MicroRNAs (miRNAs) participate in the comprehensive biological process of several cancer types. In our former study, we found that hsa-microRNA- (miR-)28-5p was downregulated, but tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activating protein zeta (14-3-3ζ or YWHAZ) was upregulated in diffuse large B-cell lymphoma (DLBCL) tissues. We predicted that YWHAZ was a target gene for hsa-miR- 28-5p using bioinformatics analysis. Our goal was to reveal the role of hsa-miR-28-5p in DLBCL. YWHAZ was tested by immunohistochemistry (IHC) in formalin-fixed paraffin-embedded (FFPE) tissues of 137 DLBCL tissues, and the expression of hsa-miR-28-5p and YWHAZ was examined by quantitative real-time polymerase chain reaction (qRT-PCR) in 15 fresh and frozen DLBCL tissues. To study the functional roles of the downregulated hsa-miR-28-5p in DLBCL, a Cell Counting Kit-8 assay was conducted to estimate cell proliferation. Transient transfection of miRNA mimics was performed to overexpress hsa-miR-28-5p, and flow cytometry was performed to examine cell apoptosis and cell cycle progression. A dual-luciferase reporter assay was employed to explore the relationship between hsa-miR-28-5p and YWHAZ. Western blotting and qRT-PCR were used to investigate the function of hsa-miR-28-5p in YWHAZ expression. hsa-miR-28-5p was found to be significantly downregulated in DLBCL tissues and cell lines. Functional studies showed that hsa-miR-28-5p overexpression inhibited cell viability and proliferation, and YWHAZ was predicted to be a target of hsa-miR-28-5p. Dual-luciferase reporter assay, Western blotting, and qRT-PCR verified that hsa-miR-28-5p negatively regulated YWHAZ expression by directly targeting its 3′ untranslated regions in DLBCL cells. hsa-miR-28-5p may suppress the growth of DLBCL cells by inhibiting YWHAZ expression. These findings could provide novel targets for DLBCL diagnosis and therapy.

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Section: Discussionmentioning

confidence: 99%

hsa-MicroRNA-28-5p Inhibits Diffuse Large B-Cell Lymphoma Cell Proliferation by Downregulating 14-3-3ζ Expression

Yan

Chen

Yang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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“…To overcome this issue, Corradi and his group used computational techniques, in combination with biophysical and biochemical techniques, to investigate a new set of promising hits with a stable scaffold at room temperature, while Iralde-Lorente and colleagues proposed a synthetic scheme of compound 14 and its chemically stable derivatives. These studies successfully identified two synthesizable and chemically stable compounds, BV01 (15) and 16 (Figure 8a) which showed antiproliferative activity against IM-resistant cells expressing the T315I Bcr-Abl mutation, and a K-562 erythroleukemia cell line at low micromolar concentrations, respectively [95,114]. Recently, a series of bivalent 14-3-3σ peptide inhibitors, 2a-d (17-20) (Figure 8b) were generated using on-resin stepwise substitution reactions on 1,3,5-triazine.…”

Section: Non-phosphonate-type Inhibitors Of 14-3-3σmentioning

confidence: 99%

14-3-3σ and Its Modulators in Cancer

Aljabal

Yap

2020

Pharmaceuticals

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14-3-3σ is an acidic homodimer protein with more than one hundred different protein partners associated with oncogenic signaling and cell cycle regulation. This review aims to highlight the crucial role of 14-3-3σ in controlling tumor growth and apoptosis and provide a detailed discussion on the structure–activity relationship and binding interactions of the most recent 14-3-3σ protein-protein interaction (PPI) modulators reported to date, which has not been reviewed previously. This includes the new fusicoccanes stabilizers (FC-NAc, DP-005), fragment stabilizers (TCF521-123, TCF521-129, AZ-003, AZ-008), phosphate-based inhibitors (IMP, PLP), peptide inhibitors (2a–d), as well as inhibitors from natural sources (85531185, 95911592). Additionally, this review will also include the discussions of the recent efforts by a different group of researchers for understanding the binding mechanisms of existing 14-3-3σ PPI modulators. The strategies and state-of-the-art techniques applied by various group of researchers in the discovery of a different chemical class of 14-3-3σ modulators for cancer are also briefly discussed in this review, which can be used as a guide in the development of new 14-3-3σ modulators in the near future.

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“…The active cavity of 14-3-3 protein is used to recognize partner proteins. Some small inhibitors and stabilizers modulate the 14-3-3 protein function by targeting this active cavity ( Zhao et al, 2011 ; Iralde-Lorente et al, 2019 ; Gigante et al, 2020 ). Theoretically, K11 and K49, which are deeply located in the active pocket, can be bound to inhibit the activity of 14-3-3 σ.…”

Section: Resultsmentioning

confidence: 99%

Exploring the Binding Mechanism of a Supramolecular Tweezer CLR01 to 14-3-3σ Protein via Well-Tempered Metadynamics

et al. 2022

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Using supramolecules for protein function regulation is an effective strategy in chemical biology and drug discovery. However, due to the presence of multiple binding sites on protein surfaces, protein function regulation via selective binding of supramolecules is challenging. Recently, the functions of 14-3-3 proteins, which play an important role in regulating intracellular signaling pathways via protein–protein interactions, have been modulated using a supramolecular tweezer, CLR01. However, the binding mechanisms of the tweezer molecule to 14-3-3 proteins are still unclear, which has hindered the development of novel supramolecules targeting the 14-3-3 proteins. Herein, the binding mechanisms of the tweezer to the lysine residues on 14-3-3σ (an isoform in 14-3-3 protein family) were explored by well-tempered metadynamics. The results indicated that the inclusion complex formed between the protein and supramolecule is affected by both kinetic and thermodynamic factors. In particular, simulations confirmed that K214 could form a strong binding complex with the tweezer; the binding free energy was calculated to be −10.5 kcal·mol−1 with an association barrier height of 3.7 kcal·mol−1. In addition, several other lysine residues on 14-3-3σ were identified as being well-recognized by the tweezer, which agrees with experimental results, although only K214/tweezer was co-crystallized. Additionally, the binding mechanisms of the tweezer to all lysine residues were analyzed by exploring the representative conformations during the formation of the inclusion complex. This could be helpful for the development of new inhibitors based on tweezers with more functions against 14-3-3 proteins via modifications of CLR01. We also believe that the proposed computational strategies can be extended to understand the binding mechanism of multi-binding sites proteins with supramolecules and will, thus, be useful toward drug design.

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Chemically stable inhibitors of 14-3-3 protein–protein interactions derived from BV02

Cited by 17 publications

References 22 publications

hsa-MicroRNA-28-5p Inhibits Diffuse Large B-Cell Lymphoma Cell Proliferation by Downregulating 14-3-3ζ Expression

hsa-MicroRNA-28-5p Inhibits Diffuse Large B-Cell Lymphoma Cell Proliferation by Downregulating 14-3-3ζ Expression

14-3-3σ and Its Modulators in Cancer

Exploring the Binding Mechanism of a Supramolecular Tweezer CLR01 to 14-3-3σ Protein via Well-Tempered Metadynamics

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