Design, synthesis and activity of BBI608 derivatives targeting on stem cells

Zhou, Qifan; Chen, Peng; Du, Fangyu; Zhou, Lu; Shi, Yajie; Du, Yang; Liu, Dongdong; Sun, Wenjiao; Zhang, Meixia; Chen, Guoliang

doi:10.1016/j.ejmech.2018.03.054

Cited by 36 publications

(17 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The third set of genes (β-catenin, SOX2, SMO and Nanog) were chosen based on other published reports of PD markers conducted using Napa in other solid tumours. 19 , 34 , 41 These hallmark stemness markers were also significantly decreased following Napa treatment in MPNST with the exception of Nanog (Fig. 5e , panel 2).…”

Section: Discussionmentioning

confidence: 87%

Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours

et al. 2021

View full text Add to dashboard Cite

Background MPNST is a rare soft-tissue sarcoma that can arise from patients with NF1. Existing chemotherapeutic and targeted agents have been unsuccessful in MPNST treatment, and recent findings implicate STAT3 and HIF1-α in driving MPNST. The DNA-binding and transcriptional activity of both STAT3 and HIF1-α is regulated by Redox factor-1 (Ref-1) redox function. A first-generation Ref-1 inhibitor, APX3330, is being tested in cancer clinical trials and could be applied to MPNST. Methods We characterised Ref-1 and p-STAT3 expression in various MPNST models. Tumour growth, as well as biomarkers of apoptosis and signalling pathways, were measured by qPCR and western blot following treatment with inhibitors of Ref-1 or STAT3. Results MPNSTs from Nf1-Arfflox/floxPostnCre mice exhibit significantly increased positivity of p-STAT3 and Ref-1 expression when malignant transformation occurs. Inhibition of Ref-1 or STAT3 impairs MPNST growth in vitro and in vivo and induces apoptosis. Genes highly expressed in MPNST patients are downregulated following inhibition of Ref-1 or STAT3. Several biomarkers downstream of Ref-1 or STAT3 were also downregulated following Ref-1 or STAT3 inhibition. Conclusions Our findings implicate a unique therapeutic approach to target important MPNST signalling nodes in sarcomas using new first-in-class small molecules for potential translation to the clinic.

show abstract

Section: Discussionmentioning

confidence: 87%

Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Currently, BBI608 is being assessed in clinical trials, and the results suggest that BBI608 is a potent anti-tumorigenic and anti-CSC drug in different tumor types[118,121-123]. To further improve the pharmacokinetic properties of BBI608 and its antitumor activity, our research team designed and synthesized a series of BBI608 derivatives that display stronger inhibitory activity than BBI608 in HepG2 cells[124].…”

Section: Csc Signaling Pathways and Inhibitorsmentioning

confidence: 99%

Targeting cancer stem cells in drug discovery: Current state and future perspectives

Zhou

Sun

et al. 2019

WJSC

View full text Add to dashboard Cite

In recent decades, cancer stem cells (CSCs) have been increasingly identified in many malignancies. CSC-related signaling pathways and their functions provide new strategies for treating cancer. The aberrant activation of related signaling pathways ( e.g ., Wnt, Notch, and Hedgehog pathways) has been linked to multiple types of malignant tumors, which makes these pathways attractive targets for cancer therapy. CSCs display many characteristic features, such as self-renewal, differentiation, high tumorigenicity, and drug resistance. Therefore, there is an urgent need to develop new therapeutic strategies to target these pathways to control stem cell replication, survival, and differentiation. Notable crosstalk occurs among different signaling pathways and potentially leads to compensatory escape. Therefore, multitarget inhibitors will be one of the main methods to overcome the drug resistance of CSCs. Many small molecule inhibitors of components of signaling pathways in CSCs have entered clinical trials, and some inhibitors, such as vismodegib, sonidegib, and glasdegib, have been approved. Tumor cells are susceptible to sonidegib and vismodegib resistance due to mutations in the Smo protein. The signal transducers and activators of transcription 3 (STAT3) inhibitor BBI608 is being evaluated in a phase III trial for a variety of cancers. Structural derivatives of BBI608 are the main focus of STAT3 inhibitor development, which is another strategy for CSC therapy. In addition to the potential pharmacological inhibitors targeting CSC-related signaling pathways, other methods of targeting CSCs are available, such as nano-drug delivery systems, mitochondrion targeting, autophagy, hyperthermia, immunotherapy, and CSC microenvironment targeting. In addition, we summarize the latest advances in the clinical development of agents targeting CSC-related signaling pathways and other methods of targeting CSCs.

show abstract

“…The mixture group did not exhibit an enhanced effect in vivo, although in vitro synergy of napabucasin and BAQ13 NPs was observed. This lack of in vivo effect was probably due to the poor solubility and inefficient delivery of napabucasin 47 . When loaded in BAQ13 NPs (BAQ13 NPs@Napabucasin), the nanoformulated napabucasin achieved a satisfactory antitumour effect by synergising with BAQ13 NPs.…”

Section: Resultsmentioning

confidence: 99%

Pharmacophore hybridisation and nanoscale assembly to discover self-delivering lysosomotropic new-chemical entities for cancer therapy

Lin

et al. 2020

Nat Commun

View full text Add to dashboard Cite

Integration of the unique advantages of the fields of drug discovery and drug delivery is invaluable for the advancement of drug development. Here we propose a self-delivering one-component new-chemical-entity nanomedicine (ONN) strategy to improve cancer therapy through incorporation of the self-assembly principle into drug design. A lysosomotropic detergent (MSDH) and an autophagy inhibitor (Lys05) are hybridised to develop bisaminoquinoline derivatives that can intrinsically form nanoassemblies. The selected BAQ12 and BAQ13 ONNs are highly effective in inducing lysosomal disruption, lysosomal dysfunction and autophagy blockade and exhibit 30-fold higher antiproliferative activity than hydroxychloroquine used in clinical trials. These single-drug nanoparticles demonstrate excellent pharmacokinetic and toxicological profiles and dramatic antitumour efficacy in vivo. In addition, they are able to encapsulate and deliver additional drugs to tumour sites and are thus promising agents for autophagy inhibition-based combination therapy. Given their transdisciplinary advantages, these BAQ ONNs have enormous potential to improve cancer therapy.

show abstract

Design, synthesis and activity of BBI608 derivatives targeting on stem cells

Cited by 36 publications

References 25 publications

Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours

Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours

Targeting cancer stem cells in drug discovery: Current state and future perspectives

Pharmacophore hybridisation and nanoscale assembly to discover self-delivering lysosomotropic new-chemical entities for cancer therapy

Contact Info

Product

Resources

About