Translating Basic Biological Research to Cancer Drug Discovery

Discovery of promising next-generation inhibitors for metastatic melanoma treatment done with help from x-ray crystallography.

Article ID: 667410

Released: 9-Jan-2017 5:05 PM EST

Source Newsroom: Department of Energy, Office of Science

  • Credit: Image courtesy of Plexxikon Inc.

    This image shows how the drug (PLX7904) binds to a specific site in the mutant BRAF protein (the rest of the image), where it has the effect of disrupting the processes that promote cancer growth. The macromolecule backbone and nearest amino acids are schematically represented, with the carbon atoms in the drug colored green. A dotted surface shows how a particular group in the PLX7904 is in close contact with the Leu505 of the aC helix.

The Science

Newswise — For those treating spreading cancerous tumors, first-generation BRAF inhibitors potentially offer a non-win situation, with the treatment effectively taking on cancers with certain genetic codes, but paradoxically stimulating secondary malignancies in certain cases. Using data from two U.S. Department of Energy (DOE) user facilities, researchers at Plexxikon visualized the atomic details of inhibitor interactions with the BRAF protein, which triggers tumor growth. Understanding the atomic details aids in designing next-generation BRAF inhibitors that suppress mutant BRAF tumor cells without activating other tumor-producing pathways.

The Impact

Next-generation BRAF inhibitors dissociate unwanted paradoxical stimulation of certain cancer cells from their effectiveness in inhibiting mutant BRAF melanoma tumor cells. Therefore, these molecules could be developed into drugs with improved clinical safety and efficacy in cancer treatment compared to approved first-generation BRAF inhibitors.

Summary

First-generation BRAF inhibitors vemurafenib (PLX4032) and dabrafenib have demonstrated clinical efficacy in treating metastatic melanoma harboring BRAF codon 600 mutations. However, occasionally these inhibitors also appear to paradoxically stimulate progression of some RAS-mutated secondary malignancies that carry the wild type BRAF gene. Using x-ray diffraction data collected from DOE’s Stanford Synchrotron Radiation Lightsource and Advanced Light Source beamlines, Plexxikon scientists have pursued the discovery of next-generation BRAF inhibitors (dubbed “paradox breakers”) that uncouple these two opposing modes of action. Their strategy was to find inhibitors that are incapable of transactivating RAF dimers and ERK signaling, which had been hypothesized to be the cause of RAF inhibitor paradox. Using structure-based drug design, a series of small molecule BRAF paradox breakers were identified. Binding of the paradox breaker to RAF generates a structural change that alters the protein’s propensity for dimerization. A clinical study to test the hypothesis that such a paradox breaker, PLX8394, can be therapeutically active with less risk of the paradox-linked side effects is currently ongoing.

Funding

Plexxikon Inc. funded this research. Crystallography data were measured at beam line 9-1 at the Stanford Synchrotron Radiation Lightsource (SLAC National Accelerator Laboratory) and at beam line 8.3.1 at the Advanced Light Source (Lawrence Berkeley National Laboratory). The SSRL Structural Molecular Biology Program is supported by the U.S. Department of Energy, Office of Science, Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences.

Publications

C. Zhang, et al., “RAF inhibitors that evade paradoxical MAPK pathway activation.” Nature 526, 583–586 (2015). [DOI: 10.1038/nature14982]

SEE ORIGINAL STUDY


Comment/Share





Chat now!