11ue
Structure of PDGFRb Kinase Domain Bound to JNJ-PDGFRBi-1
Structural highlights
DiseasePGFRB_HUMAN Note=A chromosomal aberration involving PDGFRB is found in a form of chronic myelomonocytic leukemia (CMML). Translocation t(5;12)(q33;p13) with EVT6/TEL. It is characterized by abnormal clonal myeloid proliferation and by progression to acute myelogenous leukemia (AML). Note=A chromosomal aberration involving PDGFRB may be a cause of acute myelogenous leukemia. Translocation t(5;14)(q33;q32) with TRIP11. The fusion protein may be involved in clonal evolution of leukemia and eosinophilia. Note=A chromosomal aberration involving PDGFRB may be a cause of juvenile myelomonocytic leukemia. Translocation t(5;17)(q33;p11.2) with SPECC1. Defects in PDGFRB are a cause of myeloproliferative disorder chronic with eosinophilia (MPE) [MIM:131440. A hematologic disorder characterized by malignant eosinophils proliferation. Note=A chromosomal aberration involving PDGFRB is found in many instances of myeloproliferative disorder chronic with eosinophilia. Translocation t(5;12) with ETV6 on chromosome 12 creating an PDGFRB-ETV6 fusion protein. Translocation t(5;15)(q33;q22) with TP53BP1 creating a PDGFRB-TP53BP1 fusion protein. Note=A chromosomal aberration involving PDGFRB may be the cause of a myeloproliferative disorder (MBD) associated with eosinophilia. Translocation t(1;5)(q23;q33) that forms a PDE4DIP-PDGFRB fusion protein. Note=A chromosomal aberration involving PGFRB is found in a patient with T-lymphoblastic lymphoma (T-ALL) and an associated myeloproliferative neoplasm (MPN) with eosinophilia. Translocation t(5;6)(q33-34;q23) with CEP85L. The translocation fuses the 5'-end of CEP85L (isoform 4) to the 3'-end of PDGFRB. FunctionPGFRB_HUMAN Tyrosine-protein kinase that acts as cell-surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB, and plays an essential role in the regulation of embryonic development, cell proliferation, survival, differentiation, chemotaxis and migration. Plays an essential role in blood vessel development by promoting proliferation, migration and recruitment of pericytes and smooth muscle cells to endothelial cells. Plays a role in the migration of vascular smooth muscle cells and the formation of neointima at vascular injury sites. Required for normal development of the cardiovascular system. Required for normal recruitment of pericytes (mesangial cells) in the kidney glomerulus, and for normal formation of a branched network of capillaries in kidney glomeruli. Promotes rearrangement of the actin cytoskeleton and the formation of membrane ruffles. Binding of its cognate ligands - homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFD -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PLCG1, PIK3R1, PTPN11, RASA1/GAP, CBL, SHC1 and NCK1. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to the activation of the AKT1 signaling pathway. Phosphorylation of SHC1, or of the C-terminus of PTPN11, creates a binding site for GRB2, resulting in the activation of HRAS, RAF1 and down-stream MAP kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation and activation of SRC family kinases. Promotes phosphorylation of PDCD6IP/ALIX and STAM. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] Publication Abstract from PubMedBACKGROUND: Inhalation of corticosteroids, bronchodilators, antivirals, and antibiotics is well established to treat a variety of pulmonary diseases; however, no inhaled receptor tyrosine kinase (RTK) inhibitors have so far been approved for clinical use despite the key role of RTKs in several pulmonary diseases. We describe a detailed roadmap to identify, optimize, and derisk an inhaled platelet-derived growth factor receptor (PDGFR) inhibitor with extended activity in the lungs. METHODS: In this study, stable isotopes were used to model receptor turnover in vivo, a high-resolution crystal structure was generated to support structure-based drug design and enhancement of both potency and specificity, and critical physicochemical parameters that drive lung retention were identified. Since some RTK inhibitors are linked to adverse interstitial lung disease in humans, we developed a cell painting assay that helped to eliminate compounds with non-specific effects. RESULTS: We describe the steps we took to optimize the conditions for nebulized delivery to the deep lung and confirmed that >90% of PDGFR inhibition was maintained for at least 6 hours after nebulization of a 1 mg/kg dose in rats. Finally, modeling was used to calculate the projected human dose for this molecule. CONCLUSIONS: While the focus of this article is on the identification of an inhaled PDGFR inhibitor, our approach to develop a highly potent inhaled compound that has extended lung retention to minimize systemic effects could be adopted for other RTK drug discovery or lung targeting approaches. Identification of an Inhaled Pulmonary Selective PDGFR Inhibitor with Sustained Target Engagement.,Marsboom G, Lu T, Hong Z, Holt K, Edmondson M, Huang CH, Del Rosario AM, Ibrahim S, Wong V, Harbut M, Jaensch S, Liu Z, Shi Y, Shaffer P, Abeywickrema P, Duda D, Cho JH, Diaz E, Wang W, Bell-Temin H, Riley D, Patel S, Park S, Hinke SA, Nawrocki AR, Yung LM, Schlicker Spain A, John C, Krosky D, Xu SS, Bauman DR J Aerosol Med Pulm Drug Deliv. 2026 May 8:19412711261449635. doi: , 10.1177/19412711261449635. PMID:42100928[20] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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