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Structural investigation of B-Raf paradox breaker and inducer inhibitors

(2015) JOURNAL OF MEDICINAL CHEMISTRY. 58(4). p.1818-1831
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Abstract
The V600E missense mutation in B-Raf kinase leads to an anomalous regulation of the MAPK pathway, uncontrolled cell proliferation, and initiation of tumorigenesis. While the ATP-competitive B-Raf inhibitors block the MAPK pathway in B-Raf mutant cells, they induce conformational changes to wild-type B-Raf kinase domain leading to heterodimerization with C-Raf causing a paradoxical hyperactivation of MAPK pathway. A new class of inhibitors (paradox breakers) has been developed that inhibit B-RafV600E activity without agonistically affecting the MAPK pathway in wild-type B-Raf cells. In this study, we explore the structural, conformational, and cellular effects on the B-Raf kinase domain upon binding of paradox breakers and inducers. Our results indicate that a subtle structural difference between paradox inducers and breakers leads to significant conformational differences when complexed with B-Raf. This study provides a novel insight into the activation of B-Raf by ATP-competitive inhibitors and can aid in the design of more potent and selective inhibitors without agonistic function.
Keywords
PATHWAY, ACTIVATION, MUTATIONS, BRAF, RESISTANT MELANOMA, MOLECULAR-DYNAMICS, KINASE INHIBITORS, DIMERIZATION, GROWTH, MECHANISM

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Citation

Please use this url to cite or link to this publication:

Chicago
Arora, Rohit, Michela Di Michele, Elisabeth Stes, Elien Vandermarliere, Lennart Martens, Kris Gevaert, Erika Van Heerde, et al. 2015. “Structural Investigation of B-Raf Paradox Breaker and Inducer Inhibitors.” Journal of Medicinal Chemistry 58 (4): 1818–1831.
APA
Arora, R., Di Michele, M., Stes, E., Vandermarliere, E., Martens, L., Gevaert, K., Van Heerde, E., et al. (2015). Structural investigation of B-Raf paradox breaker and inducer inhibitors. JOURNAL OF MEDICINAL CHEMISTRY, 58(4), 1818–1831.
Vancouver
1.
Arora R, Di Michele M, Stes E, Vandermarliere E, Martens L, Gevaert K, et al. Structural investigation of B-Raf paradox breaker and inducer inhibitors. JOURNAL OF MEDICINAL CHEMISTRY. 2015;58(4):1818–31.
MLA
Arora, Rohit, Michela Di Michele, Elisabeth Stes, et al. “Structural Investigation of B-Raf Paradox Breaker and Inducer Inhibitors.” JOURNAL OF MEDICINAL CHEMISTRY 58.4 (2015): 1818–1831. Print.
@article{5930762,
  abstract     = {The V600E missense mutation in B-Raf kinase leads to an anomalous regulation of the MAPK pathway, uncontrolled cell proliferation, and initiation of tumorigenesis. While the ATP-competitive B-Raf inhibitors block the MAPK pathway in B-Raf mutant cells, they induce conformational changes to wild-type B-Raf kinase domain leading to heterodimerization with C-Raf causing a paradoxical hyperactivation of MAPK pathway. A new class of inhibitors (paradox breakers) has been developed that inhibit B-RafV600E activity without agonistically affecting the MAPK pathway in wild-type B-Raf cells. In this study, we explore the structural, conformational, and cellular effects on the B-Raf kinase domain upon binding of paradox breakers and inducers. Our results indicate that a subtle structural difference between paradox inducers and breakers leads to significant conformational differences when complexed with B-Raf. This study provides a novel insight into the activation of B-Raf by ATP-competitive inhibitors and can aid in the design of more potent and selective inhibitors without agonistic function.},
  author       = {Arora, Rohit and Di Michele, Michela and Stes, Elisabeth and Vandermarliere, Elien and Martens, Lennart and Gevaert, Kris and Van Heerde, Erika and Linders, Joannes TM and Brehmer, Dirk and Jacoby, Edgar and Bonnet, Pascal},
  issn         = {0022-2623},
  journal      = {JOURNAL OF MEDICINAL CHEMISTRY},
  keyword      = {PATHWAY,ACTIVATION,MUTATIONS,BRAF,RESISTANT MELANOMA,MOLECULAR-DYNAMICS,KINASE INHIBITORS,DIMERIZATION,GROWTH,MECHANISM},
  language     = {eng},
  number       = {4},
  pages        = {1818--1831},
  title        = {Structural investigation of B-Raf paradox breaker and inducer inhibitors},
  url          = {http://dx.doi.org/10.1021/jm501667n},
  volume       = {58},
  year         = {2015},
}

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