Davis Mindy, Pragani Rajan, Popovici-Muller Janeta, Gross Stefan, Thorne Natasha, Salituro Frank, Fantin Valeria, Straley Kimberly, Su Michael, Dang Lenny, Simeonov Anton, Shen Min, Boxer Matthew B.
NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850.
Agios Pharmaceuticals, Cambridge, MA 02139, USA.
The emergence of the role of isocitrate dehydrogenase (IDH) in cancer resulted from genomic sequencing for 22 glioma genomes that found recurrent mutation of on chromosome 2q33. Subsequent sequencing of over 900 tumors revealed recurrent IDH mutations in both and in up to 70% of secondary gliomas and in ~16–17% of acute myeloid leukemia (AML) cases. The mutated residue in IDH1 is most commonly arginine 132, which is most often replaced with either histidine or cysteine. This active site mutation results in loss of activity for metabolism of isocitrate, but confers gain-of-function for the production of the oncometabolite 2-hydroxyglutarate (2-HG). Herein we describe the quantitative high throughput screening of the R132H mutant IDH1 enzyme and the subsequent medicinal chemistry optimization of the small molecule hit. The resulting probe, ML309, is capable of potent and selective inhibition of mutant IDH1 and effectively lowers cell-based production of 2-HG in a U87MG mutant glioblastoma cell line. We hope that this probe leads to important studies into the role of as an oncogene, 2HG as an oncometabolite, and can potentially provide opportunities to discover much needed therapies for glioma and AML patients in the future.
异柠檬酸脱氢酶（IDH）在癌症中的作用是通过对22个胶质瘤基因组进行基因组测序发现2q33染色体上的反复突变后才得以显现。随后对900多个肿瘤进行测序发现，高达70%的继发性胶质瘤和16%-17%的急性髓性白血病（AML）病例中，IDH均存在反复突变。IDH1中发生突变的残基最常见的是精氨酸132，它最常被组氨酸或半胱氨酸取代。这种活性位点突变导致异柠檬酸代谢活性丧失，但赋予了致癌代谢物2-羟基戊二酸（2-HG）产生的功能获得。在此，我们描述了对R132H突变型IDH1酶的定量高通量筛选以及随后对小分子命中物的药物化学优化。所得探针ML309能够有效且选择性地抑制突变型IDH1，并有效降低U87MG突变型胶质母细胞瘤细胞系中基于细胞的2-HG产生。我们希望该探针能引发对IDH作为致癌基因、2-HG作为致癌代谢物作用的重要研究，并有可能为未来发现胶质瘤和AML患者急需的治疗方法提供机会。
