6u4j
From Proteopedia
Crystal structure of IDH1 R132H mutant in complex with FT-2102
Structural highlights
Disease[IDHC_HUMAN] Defects in IDH1 are involved in the development of glioma (GLM) [MIM:137800]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Mutations affecting Arg-132 are tissue-specific, and suggest that this residue plays a unique role in the development of high-grade gliomas. Mutations of Arg-132 to Cys, His, Leu or Ser abolish magnesium binding and abolish the conversion of isocitrate to alpha-ketoglutarate. Instead, alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate. Elevated levels of R(-)-2-hydroxyglutarate are correlated with an elevated risk of malignant brain tumors. Publication Abstract from PubMedInhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe the structure-based design and optimization of quinoline lead compounds to identify FT-2102, a potent, orally bioavailable, brain penetrant, and selective mIDH1 inhibitor. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model. This compound has been selected as a candidate for clinical development in hematologic malignancies, solid tumors, and gliomas with mIDH1. Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor.,Caravella JA, Lin J, Diebold RB, Campbell AM, Ericsson A, Gustafson G, Wang Z, Castro J, Clarke A, Gotur D, Josephine HR, Katz M, Kershaw M, Yao L, Toms AV, Barr KJ, Dinsmore CJ, Walker D, Ashwell S, Lu W J Med Chem. 2020 Feb 27;63(4):1612-1623. doi: 10.1021/acs.jmedchem.9b01423. Epub , 2020 Feb 12. PMID:31971798[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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