View source for 9uhc


==FGFR1 kinase domain with a covalent inhibitor 9p==
<StructureSection load='9uhc' size='340' side='right'caption='[[9uhc]], [[Resolution|resolution]] 1.88&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9uhc]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9UHC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9UHC FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.88&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1EPE:~{N}-[1-methyl-3-[2-[1-(2-morpholin-4-ylethyl)pyrazol-4-yl]-5~{H}-pyrrolo[2,3-b]pyrazin-7-yl]indol-6-yl]propanamide'>A1EPE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9uhc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9uhc OCA], [https://pdbe.org/9uhc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9uhc RCSB], [https://www.ebi.ac.uk/pdbsum/9uhc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9uhc ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/FGFR1_HUMAN FGFR1_HUMAN] Defects in FGFR1 are a cause of Pfeiffer syndrome (PS) [MIM:[https://omim.org/entry/101600 101600]; also known as acrocephalosyndactyly type V (ACS5). PS is characterized by craniosynostosis (premature fusion of the skull sutures) with deviation and enlargement of the thumbs and great toes, brachymesophalangy, with phalangeal ankylosis and a varying degree of soft tissue syndactyly.<ref>PMID:20139426</ref> <ref>PMID:7874169</ref>   Defects in FGFR1 are the cause of hypogonadotropic hypogonadism 2 with or without anosmia (HH2) [MIM:[https://omim.org/entry/147950 147950]. A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. In some cases, it is associated with non-reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH).<ref>PMID:20139426</ref> <ref>PMID:12627230</ref> <ref>PMID:15001591</ref> <ref>PMID:15605412</ref> <ref>PMID:15845591</ref> <ref>PMID:16882753</ref> <ref>PMID:16764984</ref> <ref>PMID:16757108</ref> <ref>PMID:16606836</ref> <ref>PMID:17154279</ref>   Defects in FGFR1 are the cause of osteoglophonic dysplasia (OGD) [MIM:[https://omim.org/entry/166250 166250]; also known as osteoglophonic dwarfism. OGD is characterized by craniosynostosis, prominent supraorbital ridge, and depressed nasal bridge, as well as by rhizomelic dwarfism and nonossifying bone lesions. Inheritance is autosomal dominant.<ref>PMID:20139426</ref> <ref>PMID:15625620</ref> <ref>PMID:16470795</ref>   Defects in FGFR1 are the cause of trigonocephaly type 1 (TRIGNO1) [MIM:[https://omim.org/entry/190440 190440]. A keel-shaped deformation of the forehead resulting from premature fusion of the frontal suture. Trigonocephaly may occur also as a part of a syndrome.<ref>PMID:20139426</ref> <ref>PMID:11173846</ref>   Note=A chromosomal aberration involving FGFR1 may be a cause of stem cell leukemia lymphoma syndrome (SCLL). Translocation t(8;13)(p11;q12) with ZMYM2. SCLL usually presents as lymphoblastic lymphoma in association with a myeloproliferative disorder, often accompanied by pronounced peripheral eosinophilia and/or prominent eosinophilic infiltrates in the affected bone marrow.<ref>PMID:20139426</ref>   Note=A chromosomal aberration involving FGFR1 may be a cause of stem cell myeloproliferative disorder (MPD). Translocation t(6;8)(q27;p11) with FGFR1OP. Insertion ins(12;8)(p11;p11p22) with FGFR1OP2. MPD is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion proteins FGFR1OP2-FGFR1, FGFR1OP-FGFR1 or FGFR1-FGFR1OP may exhibit constitutive kinase activity and be responsible for the transforming activity.  Note=A chromosomal aberration involving FGFR1 may be a cause of stem cell myeloproliferative disorder (MPD). Translocation t(8;9)(p12;q33) with CEP110. MPD is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion protein CEP110-FGFR1 is found in the cytoplasm, exhibits constitutive kinase activity and may be responsible for the transforming activity.
== Function ==
[https://www.uniprot.org/uniprot/FGFR1_HUMAN FGFR1_HUMAN] Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation.<ref>PMID:20139426</ref> <ref>PMID:1379697</ref> <ref>PMID:1379698</ref> <ref>PMID:8622701</ref> <ref>PMID:8663044</ref> <ref>PMID:11353842</ref> <ref>PMID:12181353</ref> <ref>PMID:15117958</ref> <ref>PMID:16597617</ref> <ref>PMID:17623664</ref> <ref>PMID:17311277</ref> <ref>PMID:18480409</ref> <ref>PMID:19261810</ref> <ref>PMID:19224897</ref> <ref>PMID:21765395</ref> <ref>PMID:10830168</ref> <ref>PMID:19665973</ref> <ref>PMID:20133753</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Aberrant activation of fibroblast growth factor receptors (FGFRs) plays a critical role in tumorigenesis across multiple cancer types, driving the development of various FGFR inhibitors. Despite clinical advances, therapeutic efficacy remains limited by the emergence of drug resistance, primarily mediated by gatekeeper mutations in FGFRs. To overcome this challenge, we designed and synthesized a novel series of 7-(1-methyl-1H-indole-3-yl)-5H-pyrrolo[2,3-b]pyrazine derivatives as covalent pan-FGFR inhibitors targeting both wild-type and gatekeeper mutants. Compound 9p demonstrated potent nanomolar inhibitory activity against FGFR1-3 and gatekeeper mutants in biochemical and cellular assays. Structural characterization using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF-MS) and X-ray crystallography confirmed covalent binding of 9p to FGFR1. Additionally, 9p showed significant in vivo antitumor efficacy in nude mice bearing the RT112 bladder cancer xenograft model. These findings establish 9p as a promising lead for further development of FGFR-targeted anticancer therapies.

Design, Synthesis and Biological Evaluation of 7-(1-Methyl-1H-indole-3-yl)-5H-pyrrolo[2,3-b]pyrazine Derivatives as Novel Covalent pan-FGFR Inhibitors to Overcome Clinical Resistance.,Deng W, Chen X, Yan L, Xiang S, Song X, Zhang L, Li X, Zhu W, Pei J, Lin X, Patterson AV, Smaill JB, Li B, Tu Z, Zhou Y, Chen Y, Lu X J Med Chem. 2025 Sep 8. doi: 10.1021/acs.jmedchem.5c01594. PMID:40921092<ref>PMID:40921092</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 9uhc" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chen XJ]]
[[Category: Chen YH]]