Synthesis and evaluation of novel dimethylpyridazine derivatives as hedgehog signaling pathway inhibitors

Chen, Zhong; Zhu, Mingfei; Lu, Xiuhong; Wang, Hong; Zhao, Weili; Zhang, Xiongwen; Dong, Xiaochun

doi:10.1016/j.bmc.2018.04.058

Cited by 17 publications

(7 citation statements)

References 20 publications

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“…Taladegib is an antagonist of the Hedgehog ligand cell surface receptor SMO with potential antineoplastic activity. Recently, a study demonstrated the in vivo efficacy of taladegib in a mouse medulloblastoma allograft model [111].…”

Section: Smo Inhibitorsmentioning

confidence: 99%

Targeting the Hedgehog Pathway in Cancer: Current Evidence and Future Perspectives

Girardi

Barrichello

Fernandes

et al. 2019

Cells

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The Hedgehog pathway (HhP) plays an important role in normal embryonic development and its abnormal function has been linked to a variety of neoplasms. Recently, the complex mechanisms involved in this pathway have been deciphered and the cross talks with other important pathways involved in carcinogenesis have been characterized. This knowledge has led to the development of targeted therapies against key components of HhP, which culminated in the approval of vismodegib for the treatment of advanced basal cell carcinoma in 2012. Since then, other compounds have been developed and evaluated in preclinical and clinical studies with interesting results. Today, several medications against components of the HhP have demonstrated clinical activity as monotherapies and in combination with cytotoxic treatment or other targeted therapies against mitogenic pathways that are linked to the HhP. This review aims to clarify the mechanism of the HhP and the complex crosstalk with others pathways involved in carcinogenesis and to discuss both the evidence associated with the growing number of medications and combined therapies addressing this pathway and future perspectives.

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Section: Smo Inhibitorsmentioning

confidence: 99%

Targeting the Hedgehog Pathway in Cancer: Current Evidence and Future Perspectives

Girardi

Barrichello

Fernandes

et al. 2019

Cells

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“…Recently, Wang et al 98 have further optimized the structural units of taladegib by replacing the phthalazine core with dimethylpyridazine to give a scaffold 8o (Figure 8G). For region-A, exchange of 1-methyl-1H-pyrazole by a phenyl ring bearing either electron-withdrawing or electron-donating groups exhibited reduced inhibition potential compared with the parent compound.…”

Section: Recent Advances In Design Of Hh Pathway Inhibitorsmentioning

confidence: 99%

Design of Hedgehog pathway inhibitors for cancer treatment

Bariwal

Kumar

Dong

et al. 2018

Medicinal Research Reviews

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Hedgehog (Hh) signaling is involved in the initiation and progression of various cancers and is essential for embryonic and postnatal development. This pathway remains in the quiescent state in adult tissues but gets activated upon inflammation and injuries. Inhibition of Hh signaling pathway using natural and synthetic compounds has provided an attractive approach for treating cancer and inflammatory diseases. While the majority of Hh pathway inhibitors target the transmembrane protein Smoothened (SMO), some small molecules that target the signaling cascade downstream of SMO are of particular interest. Substantial efforts are being made to develop new molecules targeting various components of the Hh signaling pathway. Here, we have discussed the discovery of small molecules as Hh inhibitors from the diverse chemical background. Also, some of the recently identified natural products have been included as a separate section. Extensive structure-activity relationship (SAR) of each chemical class is the focus of this review. Also, clinically advanced molecules are discussed from the last 5 to 7 years. Nanomedicine-based delivery approaches for Hh pathway inhibitors are also discussed concisely.

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“…In mammals, this pathway can be activated when one of three ligands [Desert hedgehog, Indian hedgehog, or Sonic hedgehog (SHH)]bind to their receptors (Patched) [5]. Hedgehog receptor PTCH then relieve smoothened (SMO) and result in the translocation of the glioma-associated oncogene homolog (GLI) and the transcription of Hh target genes [6].Studies have reported that the dysregulation of the Hh pathway may lead to tumorigenesis, including hepatic carcinoma, lung cancer, pancreatic cancer, and MM [7]. Beside, activation of Hh signaling is associated with drug resistance of MM stem cells, and the drug resistance is inhibited by Hh blocking agents [8].…”

Section: Introductionmentioning

confidence: 99%

Resveratrol increases the sensitivity of multiple myeloma cells against bortezomib via Hedgehog signaling pathway

Zhou¹,

Ma²,

Jin³

et al. 2021

Trop. J. Pharm Res

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Purpose: To investigate the effect of resveratrol (RSV) on bortezomib (BTZ)-resistant multiple myeloma (MM) cells, and to elucidate the underlying mechanism of action. Methods: H929 cell lines were exposed to BTZ for 8 months to establish BTZ-resistant MM cell model. Cell proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was measured using annexin V/propidium iodide (PI) staining while cell cycle analysis was evaluated by flow cytometry. The expression of Hedgehog (Hh) signaling proteins (sonic hedgehog (SHH), smoothened (SMO), and glioma-associated oncogene homolog (GLI)) was analyzed by western blot. Results: H929R was confirmed as a MM cell line that is resistant to BTZ. RSV enhanced the sensitivity of H929R cells against BTZ via inhibition of cell viability and colony formation, induction of cell apoptosis and regulation of expression of apoptosis-related proteins. Furthermore, RSV inhibited the expression of Hh signaling proteins (p < 0.05. Conclusion: RSV enhances the sensitivity of MM cells to BTZ, partly via Hh signaling pathway. Thus, Hh pathway is a probable target for MM treatment, and RSV has potentials for use in the clinical management of MM.

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Synthesis and evaluation of novel dimethylpyridazine derivatives as hedgehog signaling pathway inhibitors

Cited by 17 publications

References 20 publications

Targeting the Hedgehog Pathway in Cancer: Current Evidence and Future Perspectives

Targeting the Hedgehog Pathway in Cancer: Current Evidence and Future Perspectives

Design of Hedgehog pathway inhibitors for cancer treatment

Resveratrol increases the sensitivity of multiple myeloma cells against bortezomib via Hedgehog signaling pathway

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