12fj

Crystal structure of 6-fluoropyrazolo[1,5-a]pyridine derivative bound to KIT

spinqualitylabelsall models 12fj, resolution 2.63Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 12fj is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.629Å Ligands: A1DJF Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease KIT_HUMAN Defects in KIT are a cause of piebald trait (PBT) [MIM:172800; also known as piebaldism. PBT is an autosomal dominant genetic developmental abnormality of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes. Defects in KIT are a cause of gastrointestinal stromal tumor (GIST) [MIM:606764. Defects in KIT have been associated with testicular germ cell tumor (TGCT) [MIM:273300. A common solid malignancy in males. Germ cell tumors of the testis constitute 95% of all testicular neoplasms. Defects in KIT are a cause of acute myelogenous leukemia (AML) [MIM:601626. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development. Note=Somatic mutations that lead to constitutive activation of KIT are detected in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the kinase domain can result in a constitutively activated kinase. Function KIT_HUMAN Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1. Publication Abstract from PubMed Mast cells play critical roles in the pathogenesis of many allergic and inflammatory diseases. KIT, a receptor tyrosine kinase, is a crucial regulator of mast cells and, in consequence, the modulation of mast cells through KIT inhibition presents a promising therapeutic approach for treating a range of chronic diseases. Clinical applications of small-molecule KIT inhibitors have been limited to oncology due to adverse effects associated with poor kinome selectivity. Here, we describe a highly selective small-molecule KIT inhibitor (7) that exhibits excellent broad kinome selectivity, with a selectivity score of S(50%) = 0.003. Data-driven investigations of structure-activity relationships and careful modulation of physicochemical properties yielded improvements in potency, selectivity, and metabolic stability. Compound 7 demonstrated promising in vivo therapeutic efficacy in an SCF-driven acute cutaneous anaphylaxis model in rodents. Discovery of a Potent, Orally Bioavailable Small-Molecule Inhibitor of Wildtype KIT with Exceptionally High Kinome Selectivity.,Chen KY, Qu S, Yan X, Moon H, Lamani M, Wang Z, Mata G, Zhu J, Schweickert PG, Sivick KE, Huang HT, Van Abbema AM, Zhao X, Green DW, Jin L, Young SW, Walters MJ, Walker NP, Leleti MR, Powers JP, Jeffrey JL J Med Chem. 2026 Jul 26. doi: 10.1021/acs.jmedchem.6c00898. PMID:42503832 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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