Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds

Niculescu‐Duvaz, Dan; Niculescu‐Duvaz, Ion; Suijkerbuijk, Bart M. J. M.; Ménard, Delphine; Zambon, Alfonso; Nourry, Arnaud; Davies, Lawrence; Manne, Helen; Friedlos, Frank; Ogilvie, Lesley; Hedley, Douglas; Takle, Andrew K.; Wilson, David M.; Pons, Jean‐François; Coulter, Tom; Kirk, Ruth; Cantariño, Neus; Whittaker, Steven R.; Marais, Richard; Springer, Caroline J.

doi:10.1016/j.bmc.2010.06.031

Cited by 27 publications

(15 citation statements)

References 13 publications

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“…In contrast, vemurafenib [20] and dabrafenib [21] bind to the DFG-in active conformation of the ATP binding site. These active conformation inhibitors are highly BRAF-selective compared to other kinases [20].…”

Section: Resultsmentioning

confidence: 99%

The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma

et al. 2017

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Structure-based drug repositioning in addition to random chemical screening is now a viable route to rapid drug development. Proteochemometric computational methods coupled with kinase assays showed that mebendazole (MBZ) binds and inhibits kinases important in cancer, especially both BRAFWT and BRAFV600E. We find that MBZ synergizes with the MEK inhibitor trametinib to inhibit growth of BRAFWT-NRASQ61K melanoma cells in culture and in xenografts, and markedly decreased MEK and ERK phosphorylation. Reverse Phase Protein Array (RPPA) and immunoblot analyses show that both trametinib and MBZ inhibit the MAPK pathway, and cluster analysis revealed a protein cluster showing strong MBZ+trametinib - inhibited phosphorylation of MEK and ERK within 10 minutes, and its direct and indirect downstream targets related to stress response and translation, including ElK1 and RSKs within 30 minutes. Downstream ERK targets for cell cycle, including cMYC, were down-regulated, consistent with S- phase suppression by MBZ+trametinib, while apoptosis markers, including cleaved caspase-3, cleaved PARP and a sub-G1 population, were all increased with time. These data suggest that MBZ, a well-tolerated off-patent approved drug, should be considered as a therapeutic option in combination with trametinib, for patients with NRASQ61mut or other non-V600E BRAF mutant melanomas.

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Section: Resultsmentioning

confidence: 99%

The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma

et al. 2017

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“…Further study indicated that both pyrazole tricyclic moiety and imidazole ring played a crucial role in exerting the bioactivity. The replacement of tricyclic pyrazole by tricyclic triazole or six‐membered ring decreased inhibitory potency, this might be attributed to the steric clash or unfavorable electrostatic interaction with BRAF binding pocket …”

Section: Imidazoles As Anticancer Agentsmentioning

confidence: 99%

Comprehensive Review in Current Developments of Imidazole-Based Medicinal Chemistry

et al. 2013

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Imidazole ring is an important five-membered aromatic heterocycle widely present in natural products and synthetic molecules. The unique structural feature of imidazole ring with desirable electron-rich characteristic is beneficial for imidazole derivatives to readily bind with a variety of enzymes and receptors in biological systems through diverse weak interactions, thereby exhibiting broad bioactivities. The related research and developments of imidazole-based medicinal chemistry have become a rapidly developing and increasingly active topic. Particularly, numerous imidazole-based compounds as clinical drugs have been extensively used in the clinic to treat various types of diseases with high therapeutic potency, which have shown the enormous development value. This work systematically gives a comprehensive review in current developments of imidazole-based compounds in the whole range of medicinal chemistry as anticancer, antifungal, antibacterial, antitubercular, anti-inflammatory, antineuropathic, antihypertensive, antihistaminic, antiparasitic, antiobesity, antiviral, and other medicinal agents, together with their potential applications in diagnostics and pathology. It is hoped that this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic imidazole-based medicinal drugs, as well as more effective diagnostic agents and pathologic probes.

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“…However, this changed when Davies et al described mutations of B-Raf in 66% of melanomas and at a lower frequency in a wide range of human solid cancers. 20 Further research revealed that approximately 2% of human malignancies carry a mutation in B-Raf, 312 with highest frequencies observed in melanoma and carcinomas of the colon, thyroid gland, ovary, and biliary tract. 21,313,314 Currently, more than 100 different B-Raf mutations were described, with V600E (formerly labeled as V599E) being by far the predominant lesion (Catalogue of Somatic Mutations in Cancer: www.sanger.ac.uk/genetics/ CGP/cosmic).…”

Section: Raf Mutations In Cancermentioning

confidence: 99%

Raf Family Kinases: Old Dogs Have Learned New Tricks

et al. 2011

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First identified in the early 1980s as retroviral oncogenes, the Raf proteins have been the objects of intense research. The discoveries 10 years later that the Raf family members (Raf-1, B-Raf, and A-Raf) are bona fide Ras effectors and upstream activators of the ubiquitous ERK pathway increased the interest in these proteins primarily because of the central role that this cascade plays in cancer development. The important role of Raf in cancer was corroborated in 2002 with the discovery of B-Raf genetic mutations in a large number of tumors. This led to intensified drug development efforts to target Raf signaling in cancer. This work yielded not only recent clinical successes but also surprising insights into the regulation of Raf proteins by homodimerization and heterodimerization. Surprising insights also came from the hunt for new Raf targets. Although MEK remains the only widely accepted Raf substrate, new kinase-independent roles for Raf proteins have emerged. These include the regulation of apoptosis by suppressing the activity of the proapoptotic kinases, ASK1 and MST2, and the regulation of cell motility and differentiation by controlling the activity of Rok-α. In this review, we discuss the regulation of Raf proteins and their role in cancer, with special focus on the interacting proteins that modulate Raf signaling. We also describe the new pathways controlled by Raf proteins and summarize the successes and failures in the development of efficient anticancer therapies targeting Raf. Finally, we also argue for the necessity of more systemic approaches to obtain a better understanding of how the Ras-Raf signaling network generates biological specificity.

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Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds

Abstract: Graphical abstract1j IC50 (BRAF) = 0.24 μM; IC50 (pERK) = 0.58 μM; GI50 (SRB) = 0.87 μM.

Cited by 27 publications

References 13 publications

The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma

The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma

Comprehensive Review in Current Developments of Imidazole-Based Medicinal Chemistry

Raf Family Kinases: Old Dogs Have Learned New Tricks

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