Characterization of a novel BBB-permeable mutant IDH1 inhibitor, DS-1001b

摘要: Abstract Background Mutations in isocitrate dehydrogenase (IDH) 1 and 2 are frequently observed glioma, acute myeloid leukemia (AML) many other cancers. While wild-type IDHs convert to α-ketoglutarate (α-KG), mutant α-KG onco-metabolite 2-hydroxyglutarate (2-HG). Inhibitors of mutated IDH1 or IDH2 showed clinical benefits were approved for AML patients, supporting IDH1/2 mutations bona fide oncogenes. However, it remains unanswered whether inhibition activity glioma shows benefits. Methods Small-molecule inhibitors synthesized tested by vitro enzymes cell-based assays. DS-1001b is a tert-butylamine salt DS-1001a. X-ray crystallography was applied get the insight mechanism. We used 14C-labelled DS-1001a check brain exposure compound. glioblastoma patient-derived xenograft (PDX) model with heterozygous IDH1R132H monitor anti-tumor DS-1001b. Results inhibited enzymatic activities IDH1R132H, IDH1R132C, wild type IC50 values 8, 11 180 nM, respectively, while did not inhibit IDH2R140Q, IDH2R172Q, (IC50 of > 10000 nM). Through analysis ternary complex NADPH, compound A, derivative, A found allosteric pocket located at dimer surface IDH1R132C "open" inactive form. treatment production 2-HG from cells 20 – 50 nM. Brain mice radioactivity [14C]DS-1001a, results suggested penetrates blood-brain barrier (BBB). Administration great reduction tumor clear effects against subcutaneous A1074 PDX IDH1R132H. Conclusions Our indicate that DS-1001b, which currently phase I trial treating (NCT03030066), BBB-permeable effective through proteins. Clinical identification NCT03030066. Legal entity responsible study Daiichi Sankyo Co., Ltd. Funding Disclosure H. Matsunaga: Full / Part-time employment: Y. Machida: Research grant (institution): M. Nakagawa: Yamaguchi: Ogawara: Shima: K. Yamagata: T. Katsumoto: A. Hattori: Itoh: Seki: Nishiya: Nakamura: Suzuki: Imaoka: RD Novare Ichimura: Sankyo. I. Kitabayashi: All authors have declared no conflicts interest.