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Innovative Small Molecules Reestablish BRAF Structure, Offering New Insights into Cancer Mutations

Innovative Small Molecules Reestablish BRAF Structure, Offering New Insights into Cancer Mutations

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New research reveals how small molecule inhibitors can restore normal BRAF structure, providing crucial insights into cancer mutations and potential therapies.

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Recent research led by Professors at the University of Montreal has uncovered how small molecule inhibitors can reset the dysfunctional BRAF protein to its normal form, shedding light on cancer mutation mechanisms. The study, published in Science, highlights that many cancers involve mutations in the BRAF protein, a key regulator within the MAPK signaling pathway. Typically, BRAF remains in an inactive state through auto-inhibition, but certain mutations cause it to adopt a conformation that mimics its active form, leading to unchecked cell proliferation.

Using advanced cryo-electron microscopy, scientists observed major structural shifts in mutated BRAF proteins, proving that these mutations enable the protein to bypass normal control mechanisms. Almost identical in structure to the active form, these mutant BRAF proteins can escape autoinhibition and drive tumor growth in various cancers such as melanoma, thyroid, colon, and lung cancers.

A pivotal discovery involved the alpha-C helix of the BRAF protein, which in mutated forms, positions itself like the active state. Researchers tested small molecules designed to target and adjust this helix, successfully converting the oncogenic form back to its inactive, auto-inhibited configuration. This breakthrough demonstrates that therapeutic targeting of specific structural elements within BRAF can restore its normal functioning.

This research deepens the understanding of how BRAF mutations promote oncogenesis and introduces potential avenues for developing advanced anti-cancer therapies aimed at reversing mutation effects. The ability to directly re-establish the protein's normal conformational state paves the way for the creation of more effective inhibitors, offering hope for personalized cancer treatments in the future.

For further details, see the publication: Hugo Lavoie et al, "BRAF oncogenic mutants evade autoinhibition through a common mechanism," Science (2025). Source: https://medicalxpress.com/news/2025-05-small-molecule-inhibitors-braf-insight.html

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