Discovery of BRAF/HDAC Dual Inhibitors Suppressing Proliferation of Human Colorectal Cancer Cells

Li, Yingjun; Huang, Yongjun; Cheng, Huimin; Xu, Fei; Qi, Ruxi; Dai, Botao; Yang, Yixin; Tu, Zhengchao; Peng, Lijie; Zhang, Zhang

doi:10.3389/fchem.2022.910353

Cited by 6 publications

(8 citation statements)

References 51 publications

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“…Overexpression of MYB in leukemias and various solid cancers such as colon and ER-positive breast cancers contributes to their development and thus represents a valuable target [34][35][36][37][38][39] . The rapid development of resistance to selective chemotherapeutics (e.g., kinase inhibitors, including RAF inhibitors) is a problem that can be overcome by addressing various targets by drugs with dual or multimodal mechanisms of action such as dual BRAF/HDAC inhibitors [40,41] . In this context, compound 2A represents a promising scaffold that can be used for further optimization and advanced stages of preclinical anticancer testing.…”

Section: Discussionmentioning

confidence: 99%

Multimodal 4-arylchromene derivatives with microtubule-destabilizing, anti-angiogenic, and MYB-inhibitory activities

Köhler¹,

Reich²,

Yusenko³

et al. 2023

Cancer Drug Resist

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Aim: Efficient and readily available anticancer drugs are sought as treatment options. For this reason, chromene derivatives were prepared using the one-pot reaction and tested for their anticancer and anti-angiogenic properties. Methods: 2-Amino-3-cyano-4-(aryl)-7-methoxy-4H-chromene compounds (2A-R) were repurposed or newly synthesized via a three-component reaction of 3-methoxyphenol, various aryl aldehydes, and malononitrile. We performed assays to study the inhibition of tumor cell growth (MTT assay), effects on microtubules (immunofluorescence), cell cycle (flow-activated cell sorting analysis), angiogenesis (zebrafish model), and MYB activity (luciferase reporter assay). Fluorescence microscopy was applied for localization studies via copper-catalyzed azide-alkyne click reaction of an alkyne-tagged drug derivative. Results: Compounds 2A-C and 2F exhibited robust antiproliferative activities against several human cancer cell lines (50% inhibitory concentrations in the low nanomolar range) and showed potent MYB inhibition. The alkyne derivative 3 was localized in the cytoplasm after only 10 min of incubation. Substantial microtubule disruption and G2/M cell-cycle arrest were observed, where compound 2F stood out as a promising microtubule-disrupting agent. The study of anti-angiogenic properties showed that 2A was the only candidate with a high potential to inhibit blood vessel formation in vivo. Conclusion: The close interplay of various mechanisms, including cell-cycle arrest, MYB inhibition, and anti-angiogenic activity, led to identifying promising multimodal anticancer drug candidates.

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Section: Discussionmentioning

confidence: 99%

Multimodal 4-arylchromene derivatives with microtubule-destabilizing, anti-angiogenic, and MYB-inhibitory activities

Köhler¹,

Reich²,

Yusenko³

et al. 2023

Cancer Drug Resist

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“…The yield of this step was recorded as high. The synthesis of the core substituted thiozole (59) was accomplished via bromination of the benzylic/alpha carbon of (58) using NBS and reacting the intermediate with 2,2,2-trimethylthioacetamide either in polar aprotic solvent like DMF or DMA [69].…”

Section: Case Study à3: Synthesis Of Dabrafenib [Trade Name Tafinlar ...mentioning

confidence: 99%

Synthetic Approaches for Pharmacologically Active Decorated Six-Membered Diazines

Najajreh,

Awwad Khoury

2023

Strategies for the Synthesis of Heterocycles and Their Applications

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Diazine alkaloid (pyridazine, pyrimidine and pyrazine) scaffold, a widespread two-nitrogen containing compounds in nature (DNA, RNA, flavors, and fragrances), constitutes a central building block for wide range of pharmacological applications. Diazines are reported to exhibit antimetabolite (antifolate and), anticancer, antibacterial, antiallergic, tyrosine kinase, antimicrobial, calcium channel antagonistic, anti-inflammatory, analgesic, antihypertensive, antileishmanial, antituberculostatic, anticonvulsant, diuretic and potassium-sparing, to antiaggressive activities. Pyridazine (1,2-diazine), pyrimidine (1,3-diazine) and pyrazine (1,4-diazine) are found as mono-systems, fused or annulated in pharmaceutical, agrochemical or materials. These six-membered heterocyclic aromatic moieties defined as privileged scaffolds constitute diverse chemical structures and as such hold substantial interest for organic, medicinal and biological chemists. This chapter will focus on elaboration of the different synthetic approaches applied in preparing pharmacologically active decorated diazines with special care on pyrimidines (non-fused substituted forms) that are endowed with clinical applications. Synthetic approaches applied in preparing selected FDA approved drugs with pyrimidine as a central unit bearing different substituents will be intensively explored. Special attention will be given to novel synthetic methodologies that served molecules with improved druglikeness and ADME-Tox properties.

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“…This treatment induced the attenuation of Wnt signaling due to proteasome-dependent degradation of the Wnt transcription factor TCF7L that was HDAC6 dependent [165]. Inhibition of HDAC6 and BRAF signaling [178] Hsp-heat shock protein 90, pMEK-phosphorylated mitogen-activated protein kinase, pERK-phosphorylated extracellular signal-regulated kinase, MAPK-mitogen-activated protein kinase, ER-endoplasmic reticulum, PARP-poly (ADP-ribose) polymerase, PI3K-phosphoinositide 3-kinases, PD-L1-programmed death-ligand 1.…”

Section: Hdac6 Inhibition In Colorectal Cancermentioning

confidence: 99%

“…In CRC harboring BRAF V600E mutations, which shows a low response rate to BRAF inhibitors due to the emergence of resistance, the novel series of hydroxamate acid- and 2-aminopyridinyl-containing compounds such as BRAF and HDAC dual-targeted inhibitors were investigated. The compounds exerted enzymatic inhibitory activities against BRAFV600E and HDAC1/6 and suppressed the proliferation of CRC cells harboring both wild-type BRAF and mutated BRAF V600E [ 178 ] ( Table 3 ). Therefore, in theory, the optimal pathway blockade can be achieved by simultaneously targeting multiple steps of the pathway.…”

Section: Hdac6 Inhibition In Colorectal Cancermentioning

confidence: 99%

Role of Histone Deacetylase 6 and Histone Deacetylase 6 Inhibition in Colorectal Cancer

Vuletić,

Mirjačić Martinović,

Spasić

2023

Pharmaceutics

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Histone deacetylase 6 (HDAC6), by deacetylation of multiple substrates and association with interacting proteins, regulates many physiological processes that are involved in cancer development and invasiveness such as cell proliferation, apoptosis, motility, epithelial to mesenchymal transition, and angiogenesis. Due to its ability to remove misfolded proteins, induce autophagy, and regulate unfolded protein response, HDAC6 plays a protective role in responses to stress and enables tumor cell survival. The scope of this review is to discuss the roles of HDCA6 and its implications for the therapy of colorectal cancer (CRC). As HDAC6 is overexpressed in CRC, correlates with poor disease prognosis, and is not essential for normal mammalian development, it represents a good therapeutic target. Selective inhibition of HDAC6 impairs growth and progression without inducing major adverse events in experimental animals. In CRC, HDAC6 inhibitors have shown the potential to reduce tumor progression and enhance the therapeutic effect of other drugs. As HDAC6 is involved in the regulation of immune responses, HDAC6 inhibitors have shown the potential to improve antitumor immunity by increasing the immunogenicity of tumor cells, augmenting immune cell activity, and alleviating immunosuppression in the tumor microenvironment. Therefore, HDAC6 inhibitors may represent promising candidates to improve the effect of and overcome resistance to immunotherapy.

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Discovery of BRAF/HDAC Dual Inhibitors Suppressing Proliferation of Human Colorectal Cancer Cells

Cited by 6 publications

References 51 publications

Multimodal 4-arylchromene derivatives with microtubule-destabilizing, anti-angiogenic, and MYB-inhibitory activities

Multimodal 4-arylchromene derivatives with microtubule-destabilizing, anti-angiogenic, and MYB-inhibitory activities

Synthetic Approaches for Pharmacologically Active Decorated Six-Membered Diazines

Role of Histone Deacetylase 6 and Histone Deacetylase 6 Inhibition in Colorectal Cancer

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