Mechanism of Dimer Selectivity and Binding Cooperativity of BRAF Inhibitors

Kernekoncepter

Understanding the mechanism behind dimer selectivity and binding cooperativity of BRAF inhibitors is crucial for developing effective cancer treatments.

Resumé

The content delves into the molecular dynamics simulations of monomeric and dimeric BRAFV600E in complex with various inhibitors to uncover the mechanism of dimer selectivity and binding cooperativity. The study reveals how dimerization restrains and shifts the αC helix inward, affecting inhibitor binding preferences. It also explains how inhibitors like PHI1 induce positive cooperativity by modulating the conformation of the αC helix and DFG motif in both protomers. The analysis provides insights into kinase signaling mechanisms and aids in designing protomer-selective RAF inhibitors.

Abstract:

• Aberrant signaling of BRAFV600E drives cancer.
• New dimer-selective RAF inhibitors developed.
• Molecular dynamics simulations reveal allostery in BRAFV600E.

Introduction:

• MAPK signaling regulates cell growth.
• Mutations in BRAF common in human tumors.
• First-generation inhibitors face drug resistance.

Data Extraction:

• "Simulations uncovered details of allostery."
• "PHI1 showed potent inhibition."

Quotations:

• "Dimer-compatible inhibitors bind αC-in conformation."
• "PHI1 stabilizes αC helix differently than Ponatinib."

Results and Discussion:

• Dimerization restrains αC helix, increases DFG flexibility.
• PHI1 induces larger entropic penalty for monomer binding.
• Positive cooperativity due to allosteric modulation by PHI1.

Statistik

Simulations uncovered details of allostery.
PHI1 showed potent inhibition.

Citater

"Dimer-compatible inhibitors bind αC-in conformation."
"PHI1 stabilizes αC helix differently than Ponatinib."

Vigtigste indsigter udtrukket fra

Mechanism of Dimer Selectivity and Binding Cooperativity of BRAF inhibitors

by Clayton,J., ... kl. www.biorxiv.org 12-12-2023

https://www.biorxiv.org/content/10.1101/2023.12.12.571293v1

Dybere Forespørgsler

How does understanding dimer selectivity impact cancer treatment

Understanding dimer selectivity in the context of cancer treatment is crucial for developing more effective therapies. Dimerization of proteins like BRAFV600E plays a significant role in driving cancer progression by promoting aberrant signaling pathways. Current FDA-approved RAF inhibitors target the monomeric form of BRAFV600E but face challenges with tumor resistance due to adaptive mechanisms involving dimer formation. By elucidating the mechanism of dimer selectivity, researchers can design inhibitors that specifically target the dimeric form of BRAFV600E, overcoming resistance and improving treatment outcomes for patients with cancers driven by this mutation.

What are potential drawbacks or limitations of using dimer-selective inhibitors

While dimer-selective inhibitors offer promise in targeting specific forms of proteins involved in cancer, there are potential drawbacks and limitations to consider. One limitation is related to off-target effects, as these inhibitors may also interact with other proteins or pathways when designed to selectively bind dimers. Additionally, the complexity of protein-protein interactions within cellular signaling networks could lead to unforeseen consequences when targeting specific conformations such as dimers. Moreover, developing selective inhibitors may be challenging and time-consuming compared to broad-spectrum drugs that target multiple forms of a protein.

How can the findings on kinase signaling be applied to other diseases or conditions

The findings on kinase signaling from studies on BRAFV600E can have broader implications beyond cancer treatment and be applied to other diseases or conditions involving dysregulated kinase activity. Kinases play essential roles in various cellular processes beyond cancer, including inflammation, immune response modulation, and neurological disorders. Understanding how kinases function at a molecular level and how their activity can be modulated through inhibitor binding provides insights into potential therapeutic strategies for diverse diseases where kinase dysregulation contributes to pathogenesis. By leveraging this knowledge across different disease contexts, researchers can develop targeted therapies tailored to specific molecular mechanisms underlying each condition's pathology.