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5c9c

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Revision as of 21:49, 15 October 2015

CRYSTAL STRUCTURE OF BRAF(V600E) IN COMPLEX WITH LY3009120 COMPND

Structural highlights

5c9c is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

Disease

[BRAF_HUMAN] Note=Defects in BRAF are found in a wide range of cancers.^[1] Defects in BRAF may be a cause of colorectal cancer (CRC) [MIM:114500].^[2] Defects in BRAF are involved in lung cancer (LNCR) [MIM:211980]. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis.^[3] ^[4] Defects in BRAF are involved in non-Hodgkin lymphoma (NHL) [MIM:605027]. NHL is a cancer that starts in cells of the lymph system, which is part of the body's immune system. NHLs can occur at any age and are often marked by enlarged lymph nodes, fever and weight loss.^[5] ^[6] Defects in BRAF are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM:115150]; also known as cardio-facio-cutaneous syndrome. CFC syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. The inheritance of CFC syndrome is autosomal dominant.^[7] Defects in BRAF are the cause of Noonan syndrome type 7 (NS7) [MIM:613706]. Noonan syndrome is a disorder characterized by facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears. Other features can include short stature, a short neck with webbing or redundancy of skin, cardiac anomalies, deafness, motor delay and variable intellectual deficits.^[8] ^[9] Defects in BRAF are the cause of LEOPARD syndrome type 3 (LEOPARD3) [MIM:613707]. LEOPARD3 is a disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness.^[10] ^[11] Note=A chromosomal aberration involving BRAF is found in pilocytic astrocytomas. A tandem duplication of 2 Mb at 7q34 leads to the expression of a KIAA1549-BRAF fusion protein with a constitutive kinase activity and inducing cell transformation.^[12]

Function

[BRAF_HUMAN] Involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May play a role in the postsynaptic responses of hippocampal neuron.

Publication Abstract from PubMed

LY3009120 is a pan-RAF and RAF dimer inhibitor that inhibits all RAF isoforms and occupies both protomers in RAF dimers. Biochemical and cellular analyses revealed that LY3009120 inhibits ARAF, BRAF, and CRAF isoforms with similar affinity, while vemurafenib or dabrafenib have little or modest CRAF activity compared to their BRAF activities. LY3009120 induces BRAF-CRAF dimerization but inhibits the phosphorylation of downstream MEK and ERK, suggesting that it effectively inhibits the kinase activity of BRAF-CRAF heterodimers. Further analyses demonstrated that LY3009120 also inhibits various forms of RAF dimers including BRAF or CRAF homodimers. Due to these unique properties, LY3009120 demonstrates minimal paradoxical activation, inhibits MEK1/2 phosphorylation, and exhibits anti-tumor activities across multiple models carrying KRAS, NRAS, or BRAF mutation.

Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers.,Peng SB, Henry JR, Kaufman MD, Lu WP, Smith BD, Vogeti S, Rutkoski TJ, Wise S, Chun L, Zhang Y, Van Horn RD, Yin T, Zhang X, Yadav V, Chen SH, Gong X, Ma X, Webster Y, Buchanan S, Mochalkin I, Huber L, Kays L, Donoho GP, Walgren J, McCann D, Patel P, Conti I, Plowman GD, Starling JJ, Flynn DL Cancer Cell. 2015 Sep 14;28(3):384-98. doi: 10.1016/j.ccell.2015.08.002. Epub, 2015 Sep 3. PMID:26343583^[13]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008 Nov 1;68(21):8673-7. doi: 10.1158/0008-5472.CAN-08-2097. PMID:18974108 doi:10.1158/0008-5472.CAN-08-2097
↑ Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008 Nov 1;68(21):8673-7. doi: 10.1158/0008-5472.CAN-08-2097. PMID:18974108 doi:10.1158/0008-5472.CAN-08-2097
↑ Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008 Nov 1;68(21):8673-7. doi: 10.1158/0008-5472.CAN-08-2097. PMID:18974108 doi:10.1158/0008-5472.CAN-08-2097
↑ Naoki K, Chen TH, Richards WG, Sugarbaker DJ, Meyerson M. Missense mutations of the BRAF gene in human lung adenocarcinoma. Cancer Res. 2002 Dec 1;62(23):7001-3. PMID:12460919
↑ Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008 Nov 1;68(21):8673-7. doi: 10.1158/0008-5472.CAN-08-2097. PMID:18974108 doi:10.1158/0008-5472.CAN-08-2097
↑ Lee JW, Yoo NJ, Soung YH, Kim HS, Park WS, Kim SY, Lee JH, Park JY, Cho YG, Kim CJ, Ko YH, Kim SH, Nam SW, Lee JY, Lee SH. BRAF mutations in non-Hodgkin's lymphoma. Br J Cancer. 2003 Nov 17;89(10):1958-60. PMID:14612909 doi:10.1038/sj.bjc.6601371
↑ Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008 Nov 1;68(21):8673-7. doi: 10.1158/0008-5472.CAN-08-2097. PMID:18974108 doi:10.1158/0008-5472.CAN-08-2097
↑ Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008 Nov 1;68(21):8673-7. doi: 10.1158/0008-5472.CAN-08-2097. PMID:18974108 doi:10.1158/0008-5472.CAN-08-2097
↑ Sarkozy A, Carta C, Moretti S, Zampino G, Digilio MC, Pantaleoni F, Scioletti AP, Esposito G, Cordeddu V, Lepri F, Petrangeli V, Dentici ML, Mancini GM, Selicorni A, Rossi C, Mazzanti L, Marino B, Ferrero GB, Silengo MC, Memo L, Stanzial F, Faravelli F, Stuppia L, Puxeddu E, Gelb BD, Dallapiccola B, Tartaglia M. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Hum Mutat. 2009 Apr;30(4):695-702. doi: 10.1002/humu.20955. PMID:19206169 doi:10.1002/humu.20955
↑ Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008 Nov 1;68(21):8673-7. doi: 10.1158/0008-5472.CAN-08-2097. PMID:18974108 doi:10.1158/0008-5472.CAN-08-2097
↑ Sarkozy A, Carta C, Moretti S, Zampino G, Digilio MC, Pantaleoni F, Scioletti AP, Esposito G, Cordeddu V, Lepri F, Petrangeli V, Dentici ML, Mancini GM, Selicorni A, Rossi C, Mazzanti L, Marino B, Ferrero GB, Silengo MC, Memo L, Stanzial F, Faravelli F, Stuppia L, Puxeddu E, Gelb BD, Dallapiccola B, Tartaglia M. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Hum Mutat. 2009 Apr;30(4):695-702. doi: 10.1002/humu.20955. PMID:19206169 doi:10.1002/humu.20955
↑ Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, Collins VP. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 2008 Nov 1;68(21):8673-7. doi: 10.1158/0008-5472.CAN-08-2097. PMID:18974108 doi:10.1158/0008-5472.CAN-08-2097
↑ Peng SB, Henry JR, Kaufman MD, Lu WP, Smith BD, Vogeti S, Rutkoski TJ, Wise S, Chun L, Zhang Y, Van Horn RD, Yin T, Zhang X, Yadav V, Chen SH, Gong X, Ma X, Webster Y, Buchanan S, Mochalkin I, Huber L, Kays L, Donoho GP, Walgren J, McCann D, Patel P, Conti I, Plowman GD, Starling JJ, Flynn DL. Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers. Cancer Cell. 2015 Sep 14;28(3):384-98. doi: 10.1016/j.ccell.2015.08.002. Epub, 2015 Sep 3. PMID:26343583 doi:http://dx.doi.org/10.1016/j.ccell.2015.08.002

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5c9c"

Categories: Non-specific serine/threonine protein kinase | Abendroth, J | Chun, L | Edwards, T | Transferase-transferase inhibitor complex

@@ Line 5: / Line 5: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4Z5:1-(3,3-DIMETHYLBUTYL)-3-{2-FLUORO-4-METHYL-5-[7-METHYL-2-(METHYLAMINO)PYRIDO[2,3-D]PYRIMIDIN-6-YL]PHENYL}UREA'>4Z5</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5c9c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5c9c OCA], [http://www.rcsb.org/pdb/explore.do?structureId=5c9c RCSB], [http://www.ebi.ac.uk/pdbsum/5c9c PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5c9c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5c9c OCA], [http://pdbe.org/5c9c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5c9c RCSB], [http://www.ebi.ac.uk/pdbsum/5c9c PDBsum]</span></td></tr>
 </table>
 == Disease ==
@@ Line 13: / Line 13: @@
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
-The RAS-RAF-MEK-MAPK cascade is an essential signaling pathway, with activation typically mediated through cell surface receptors. The kinase inhibitors vemurafenib and dabrafenib, which target oncogenic BRAF V600E, have shown significant clinical efficacy in melanoma patients harboring this mutation. Because of paradoxical pathway activation, both agents were demonstrated to promote growth and metastasis of tumor cells with RAS mutations in preclinical models and are contraindicated for treatment of cancer patients with BRAF WT background, including patients with KRAS or NRAS mutations. In order to eliminate the issues associated with paradoxical MAPK pathway activation and to provide therapeutic benefit to patients with RAS mutant cancers, we sought to identify a compound not only active against BRAF V600E but also wild type BRAF and CRAF. On the basis of its superior in vitro and in vivo profile, compound 13 was selected for further development and is currently being evaluated in phase I clinical studies.
+LY3009120 is a pan-RAF and RAF dimer inhibitor that inhibits all RAF isoforms and occupies both protomers in RAF dimers. Biochemical and cellular analyses revealed that LY3009120 inhibits ARAF, BRAF, and CRAF isoforms with similar affinity, while vemurafenib or dabrafenib have little or modest CRAF activity compared to their BRAF activities. LY3009120 induces BRAF-CRAF dimerization but inhibits the phosphorylation of downstream MEK and ERK, suggesting that it effectively inhibits the kinase activity of BRAF-CRAF heterodimers. Further analyses demonstrated that LY3009120 also inhibits various forms of RAF dimers including BRAF or CRAF homodimers. Due to these unique properties, LY3009120 demonstrates minimal paradoxical activation, inhibits MEK1/2 phosphorylation, and exhibits anti-tumor activities across multiple models carrying KRAS, NRAS, or BRAF mutation.
-Discovery of 1-(3,3-Dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3- d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a Pan-RAF Inhibitor with Minimal Paradoxical Activation and Activity against BRAF or RAS Mutant Tumor Cells.,Henry JR, Kaufman MD, Peng SB, Ahn YM, Caldwell TM, Vogeti L, Telikepalli H, Lu WP, Hood MM, Rutkoski TJ, Smith BD, Vogeti S, Miller D, Wise SC, Chun L, Zhang X, Zhang Y, Kays L, Hipskind PA, Wrobleski AD, Lobb KL, Clay JM, Cohen JD, Walgren JL, McCann D, Patel P, Clawson DK, Guo S, Manglicmot D, Groshong C, Logan C, Starling JJ, Flynn DL J Med Chem. 2015 May 28;58(10):4165-79. doi: 10.1021/acs.jmedchem.5b00067. Epub, 2015 May 12. PMID:25965804<ref>PMID:25965804</ref>
+Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers.,Peng SB, Henry JR, Kaufman MD, Lu WP, Smith BD, Vogeti S, Rutkoski TJ, Wise S, Chun L, Zhang Y, Van Horn RD, Yin T, Zhang X, Yadav V, Chen SH, Gong X, Ma X, Webster Y, Buchanan S, Mochalkin I, Huber L, Kays L, Donoho GP, Walgren J, McCann D, Patel P, Conti I, Plowman GD, Starling JJ, Flynn DL Cancer Cell. 2015 Sep 14;28(3):384-98. doi: 10.1016/j.ccell.2015.08.002. Epub, 2015 Sep 3. PMID:26343583<ref>PMID:26343583</ref>
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 5c9c" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

5c9c

From Proteopedia

Revision as of 21:49, 15 October 2015

CRYSTAL STRUCTURE OF BRAF(V600E) IN COMPLEX WITH LY3009120 COMPND

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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