Molecular insights to the bioactive form of BV02 , a reference inhibitor of 14-3-3σ protein–protein interactions

Valensin, Daniela; Cau, Ylenia; Calandro, Pierpaolo; Vignaroli, Giulia; Iacono, Lucia Dello; Chiariello, Mario; Mori, Mattia; Botta, Maurizio

doi:10.1016/j.bmcl.2015.12.066

Cited by 12 publications

(16 citation statements)

References 21 publications

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“…Compound 13 was reported to be able to disrupt the interaction between 14-3-3σ and c-Abl protein and subsequently promotes c-Abl translocation into the nucleus and provide antiproliferative effects in CML cells expressing the imatinib-resistant T315I Bcr-Abl construct [111,112]. Unfortunately, further studies using NMR techniques showed that 13 undergoes spontaneous chemical rearrangement at room temperature and exists in equilibrium between 2-carbamoyl benzoic form (13) and its bioactive phthalimidic form, 9 (14) [95,113]. 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.…”

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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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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“…Compared to the parent 14-3-3 PPI inhibitor 9 , chemical stability at physiological conditions was remarkably improved by removing one of the carbonyl groups from the phthalimide moiety (compound 1 ), as observed by NMR spectroscopy ( Figure 2 ). Indeed, no variations in peaks chemical shift and multiplicity within the aromatic region of the NMR spectrum of 1 in DMSO/D 2 O 70:30 was observed, also after 24 h. According to the previous analysis of the chemical stability of 9 12 , this region was selected as the most sensible to the hydration/dehydration pathway shown in Figure 1 . Besides NMR, chemical identity of compound 1 was confirmed also by mass spectrometry after 24 h.…”

Section: Resultsmentioning

confidence: 89%

“…Notwithstanding, the molecule suffers from chemical instability in aqueous buffer, which leads to the phthalimide derivative 9 by means of a hydration/dehydration pathway ( Figure 1 ) 11 . Thus, the characterisation of the mechanism of action of BV02 has required a combination of chemical, computational, and spectroscopic studies, which have led to the identification of the phthalimide 9 as the bioactive form of BV02 in physiological conditions, although the persistency of 9 was found to be strictly dependent on the pH as well as the incubation time 12 .…”

Section: Introductionmentioning

confidence: 99%

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

Iralde-Lorente

Cau

Clementi

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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14-3-3 are regulatory proteins that through protein-protein interactions (PPI) with numerous binding partners could be involved in several human diseases, including cancer, neurodegenerative disorders, and pathogens infections. Following our research interest in the development of 14-3-3 PPI inhibitors, here we exploited the privileged 4-aminoantipyrine scaffold in the design and synthesis of some derivatives endowed with antiproliferative activity against K-562 cells, and capable of binding to recombinant 14-3-3r as evidenced by NMR spectroscopy. The binding mode was further explored by molecular modelling, while coupling confocal microscopy with intensitometric analysis showed that compound 1 was able to promote the nuclear translocation of c-Abl at low micromolar concentrations. Overall, 1 is chemically stable compared to parent 14-3-3 PPI inhibitors, and thus emerged as a confirmed hit for further development.

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“…NMR is a powerful tool to monitor the chemical stability of bioactive substances in solution and to clarify their possible degradation pathway 57 . Due to limited water solubility, NMR-based kinetic studies of GANT61 were performed in a 1:1 mixture of EtOH- d 6 and deuterated PBS buffer prepared by mixing Na 2 DPO 4 and KD 2 PO 4 in D 2 O and adding proper amounts of NaCl and KCl (pD = 7.4).…”

Section: Resultsmentioning

confidence: 99%

Chemical, computational and functional insights into the chemical stability of the Hedgehog pathway inhibitor GANT61

Calcaterra

Iovine

Botta

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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This work aims at elucidating the mechanism and kinetics of hydrolysis of GANT61, the first and most-widely used inhibitor of the Hedgehog (Hh) signalling pathway that targets Glioma-associated oncogene homologue (Gli) proteins, and at confirming the chemical nature of its bioactive form. GANT61 is poorly stable under physiological conditions and rapidly hydrolyses into an aldehyde species (GANT61-A), which is devoid of the biological activity against Hh signalling, and a diamine derivative (GANT61-D), which has shown inhibition of Gli-mediated transcription. Here, we combined chemical synthesis, NMR spectroscopy, analytical studies, molecular modelling and functional cell assays to characterise the GANT61 hydrolysis pathway. Our results show that GANT61-D is the bioactive form of GANT61 in NIH3T3 Shh-Light II cells and SuFu−/− mouse embryonic fibroblasts, and clarify the structural requirements for GANT61-D binding to Gli1. This study paves the way to the design of GANT61 derivatives with improved potency and chemical stability.

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Molecular insights to the bioactive form of BV02 , a reference inhibitor of 14-3-3σ protein–protein interactions

Cited by 12 publications

References 21 publications

14-3-3σ and Its Modulators in Cancer

14-3-3σ and Its Modulators in Cancer

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

Chemical, computational and functional insights into the chemical stability of the Hedgehog pathway inhibitor GANT61

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