Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity
James Tsai,John T. Lee,Weiru Wang,Jiazhong Zhang,Hanna Cho,Shumeye Mamo,Ryan Bremer,Sam Gillette,Jun Kong,Nikolas K. Haass,Katrin Sproesser,Ling Li,Keiran S.M. Smalley,D. Fong,Yong-Liang Zhu,Adhirai Marimuthu,Hoa Nguyen,Billy Lam,Jennifer S. Liu,Ivana Cheung,Julie Rice,Yoshihisa Suzuki,Catherine Luu,Calvin Settachatgul,Rafe Shellooe,John Cantwell,Sung-Hou Kim,Joseph Schlessinger,Kam Y. J. Zhang,Brian L. West,Ben Powell,Gaston Habets,Chao Zhang,Prabha N. Ibrahim,Peter Hirth,Dean R. Artis,Meenhard Herlyn,Gideon Bollag +37 more
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TLDR
PLX4720, a 7-azaindole derivative that inhibits B-RafV600E with an IC50 of 13 nM, defines a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays and represents the entire discovery process from initial identification through structural and biological studies in animal models to a promising therapeutic for testing in cancer patients bearing B- RafV 600E-driven tumors.Abstract:
BRAF(V600E) is the most frequent oncogenic protein kinase mutation known. Furthermore, inhibitors targeting "active" protein kinases have demonstrated significant utility in the therapeutic repertoire against cancer. Therefore, we pursued the development of specific kinase inhibitors targeting B-Raf, and the V600E allele in particular. By using a structure-guided discovery approach, a potent and selective inhibitor of active B-Raf has been discovered. PLX4720, a 7-azaindole derivative that inhibits B-Raf(V600E) with an IC(50) of 13 nM, defines a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays. PLX4720 preferentially inhibits the active B-Raf(V600E) kinase compared with a broad spectrum of other kinases, and potent cytotoxic effects are also exclusive to cells bearing the V600E allele. Consistent with the high degree of selectivity, ERK phosphorylation is potently inhibited by PLX4720 in B-Raf(V600E)-bearing tumor cell lines but not in cells lacking oncogenic B-Raf. In melanoma models, PLX4720 induces cell cycle arrest and apoptosis exclusively in B-Raf(V600E)-positive cells. In B-Raf(V600E)-dependent tumor xenograft models, orally dosed PLX4720 causes significant tumor growth delays, including tumor regressions, without evidence of toxicity. The work described here represents the entire discovery process, from initial identification through structural and biological studies in animal models to a promising therapeutic for testing in cancer patients bearing B-Raf(V600E)-driven tumors.read more
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Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation
Paul B. Chapman,Axel Hauschild,Caroline Robert,John B. A. G. Haanen,Paolo A. Ascierto,James Larkin,Reinhard Dummer,Claus Garbe,Alessandro Testori,Michele Maio,David W. Hogg,Paul Lorigan,Céleste Lebbé,Thomas Jouary,Dirk Schadendorf,Antoni Ribas,Jeffrey A. Sosman,John M. Kirkwood,Brigitte Dréno,K. B. Nolop,Jiang Li,B. Nelson,Jeannie Hou,Richard J. Lee,Keith T. Flaherty,Grant A. McArthur +25 more
TL;DR: Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation in a phase 3 randomized clinical trial.
Journal ArticleDOI
The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity
Jordi Barretina,Giordano Caponigro,Nicolas Stransky,Kavitha Venkatesan,Adam A. Margolin,Adam A. Margolin,Sungjoon Kim,Christine D. Wilson,Joseph Lehar,Gregory V. Kryukov,Dmitriy Sonkin,Anupama Reddy,Manway Liu,Lauren Murray,Michael F. Berger,Michael F. Berger,John Monahan,Paula Morais,Jodi Meltzer,Adam Korejwa,Judit Jané-Valbuena,Judit Jané-Valbuena,Felipa A. Mapa,Joseph Thibault,Eva Bric-Furlong,Pichai Raman,Aaron Shipway,Ingo H. Engels,Jill Cheng,Guoying K. Yu,Jianjun Yu,Peter Aspesi,Melanie de Silva,Kalpana Jagtap,Michael D. Jones,Li Wang,Charlie Hatton,Emanuele Palescandolo,Supriya Gupta,Scott Mahan,Carrie Sougnez,Robert C. Onofrio,Ted Liefeld,Laura E. MacConaill,Wendy Winckler,Michael R. Reich,Nanxin Li,Jill P. Mesirov,Stacey Gabriel,Gad Getz,Kristin G. Ardlie,Vivien W. Chan,Vic E. Myer,Barbara L. Weber,Jeffrey A. Porter,Markus Warmuth,Peter Finan,Jennifer L. Harris,Matthew Meyerson,Matthew Meyerson,Todd R. Golub,Michael Morrissey,William R. Sellers,Robert Schlegel,Levi A. Garraway,Levi A. Garraway +65 more
TL;DR: The results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents and the generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of ‘personalized’ therapeutic regimens.
Journal ArticleDOI
Inhibition of mutated, activated BRAF in metastatic melanoma.
Keith T. Flaherty,Igor Puzanov,Kevin B. Kim,Antoni Ribas,Grant A. McArthur,Jeffrey A. Sosman,Peter J. O'Dwyer,Richard J. Lee,Joseph F. Grippo,K. B. Nolop,Paul B. Chapman +10 more
TL;DR: Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients.
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Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001-2011).
Jiang Wang,María Sánchez-Roselló,José Luis Aceña,Carlos del Pozo,Alexander E. Sorochinsky,Alexander E. Sorochinsky,Alexander E. Sorochinsky,Santos Fustero,Vadim A. Soloshonok,Vadim A. Soloshonok,Hong Liu +10 more
TL;DR: Introduced to the Market in the Last Decade (2001−2011) Jiang Wang,† María Sańchez-Rosello,́‡,§ Jose ́ Luis Aceña, Carlos del Pozo,‡ and Hong Liu.
Journal ArticleDOI
Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation
Ramin Nazarian,Hubing Shi,Qi Wang,Xiangju Kong,Richard C. Koya,Hane Lee,Zugen Chen,Mi Kyung Lee,Narsis Attar,Hooman Sazegar,Thinle Chodon,Stanley F. Nelson,Grant A. McArthur,Jeffrey A. Sosman,Antoni Ribas,Roger S. Lo +15 more
TL;DR: It is shown that melanomas escape B-RAF(V600E) targeting not through secondary B-RF(V 600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.
References
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Mutations of the BRAF gene in human cancer
Helen Davies,Graham R. Bignell,Charles Cox,Philip J. Stephens,Sarah Edkins,S. M. Clegg,Jon W. Teague,Hayley Woffendin,Mathew J. Garnett,William Bottomley,Neil Davis,Ed Dicks,Rebecca Ewing,Yvonne Floyd,Kristian Gray,S. Hall,Rachel Hawes,Jaime Hughes,Vivian Kosmidou,Andrew Menzies,Catherine Mould,Adrian Parker,Claire Stevens,Stephen Watt,Steven Hooper,Rebecca Wilson,Hiran Jayatilake,Barry A. Gusterson,Colin Cooper,Janet Shipley,Darren Hargrave,Kathy Pritchard-Jones,Norman J. Maitland,Georgia Chenevix-Trench,Gregory J. Riggins,Darell D. Bigner,Giuseppe Palmieri,Antonio Cossu,Adrienne M. Flanagan,Andrew G. Nicholson,Judy W. C. Ho,Suet Yi Leung,Siu Tsan Yuen,Barbara L. Weber,Hilliard F. Seigler,Timothy L. Darrow,Hugh Paterson,Richard Marais,Christopher J. Marshall,Richard Wooster,Michael R. Stratton,P. Andrew Futreal +51 more
TL;DR: BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers, with a single substitution (V599E) accounting for 80%.
Journal ArticleDOI
BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis
Scott Wilhelm,Christopher A. Carter,LiYa Tang,Dean Wilkie,Angela McNabola,Hong Rong,Charles Chen,Xiaomei Zhang,Patrick Vincent,Mark McHugh,Yichen Cao,Jaleel Shujath,Susan Gawlak,Deepa Eveleigh,Bruce Rowley,Li Liu,Lila Adnane,Mark Lynch,Daniel Auclair,Ian W. Taylor,Rich Gedrich,Andrei Voznesensky,Bernd Riedl,Leonard Post,Gideon Bollag,Pamela A. Trail +25 more
TL;DR: Data demonstrate that BAY 43-9006 is a novel dual action RAF kinase and VEGFR inhibitor that targets tumor cell proliferation and tumor angiogenesis.
Journal ArticleDOI
Mechanism of Activation of the Raf-Erk Signaling Pathway by Oncogenic Mutations of B-Raf
Paul T C Wan,Mathew J. Garnett,S. Mark Roe,Sharlene Lee,Dan Niculescu-Duvaz,Valerie M. Good,Cancer Genome,C. Michael Jones,Christopher J. Marshall,Caroline J. Springer,David Barford,Richard Marais +11 more
TL;DR: The high activity mutants signal to ERK by directly phosphorylating MEK, whereas the impaired activity mutants stimulate MEK by activating endogenous C-RAF, possibly via an allosteric or transphosphorylation mechanism.
Journal ArticleDOI
BRAFE600-associated senescence-like cell cycle arrest of human naevi
Chrysiis Michaloglou,Liesbeth C.W. Vredeveld,Maria S. Soengas,Christophe Denoyelle,Thomas Kuilman,Chantal M.A.M. van der Horst,Donne Majoor,Jerry W. Shay,Wolter J. Mooi,Daniel S. Peeper +9 more
TL;DR: It is shown that sustained BRAFV600E expression in human melanocytes induces cell cycle arrest, which is accompanied by the induction of both p16INK4a and senescence-associated acidic β-galactosidase (SA-β-Gal) activity, a commonly usedsenescence marker.
Journal ArticleDOI
High frequency of BRAF mutations in nevi.
Pamela M. Pollock,Ursula Harper,Katherine S. Hansen,Laura M. Yudt,Mitchell S. Stark,Christiane M. Robbins,Tracy Moses,Galen Hostetter,Urs Wagner,John W. Kakareka,Ghadi Salem,Tom Pohida,Peter J. Heenan,Paul H. Duray,Olli Kallioniemi,Nicholas K. Hayward,Jeffrey M. Trent,Paul S. Meltzer +17 more
TL;DR: In this article, the authors evaluated the timing of mutations in BRAF during melanocytic neoplasia and found that mutations resulted in the V599E amino acid substitution in 41 of 60 (68%) melanoma metastases, 4 of 5 (80%) primary melanomas and, unexpectedly, in 63 of 77 (82%) nevi.
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