1774 - Characterization of a novel BBB-permeable mutant IDH1 inhibitor, DS-1001b.

Background

Mutations in isocitrate dehydrogenase (IDH) 1 and 2 are frequently observed in glioma, acute myeloid leukemia (AML) and many other cancers. While wild-type IDHs convert isocitrate to α-ketoglutarate (α-KG), mutant IDHs convert α-KG to onco-metabolite 2-hydroxyglutarate (2-HG). Inhibitors of mutated IDH1 or IDH2 showed clinical benefits and were approved for AML patients, supporting IDH1/2 mutations are bona fide oncogenes. However, it remains unanswered whether inhibition of IDH1 mutant activity in glioma shows clinical benefits.

Methods

Small-molecule inhibitors for mutant IDH1 were synthesized and tested by in vitro IDH1 mutant enzymes and cell-based assays. DS-1001b is a tert-butylamine salt of DS-1001a. X-ray crystallography was applied to get the insight of inhibition mechanism. We used ¹⁴C-labelled DS-1001a to check the brain exposure of the compound. We used a glioblastoma patient-derived xenograft (PDX) model with heterozygous IDH1R132H to monitor the anti-tumor activity of DS-1001b.

Results

DS-1001b inhibited the enzymatic activities of IDH1R132H, IDH1R132C, and wild type IDH1 with IC₅₀ values of 8, 11 and 180 nM, respectively, while it did not inhibit IDH2R140Q, IDH2R172Q, or wild type IDH2 (IC₅₀ values of > 10000 nM). Through the analysis of X-ray crystallography of the ternary complex of IDH1R132C, NADPH, and compound A, a DS-1001b derivative, compound A was found in the allosteric pocket located at the dimer surface and IDH1R132C was in "open" inactive form. DS-1001b treatment inhibited production of 2-HG from cells with IDH1R132H or IDH1R132C at 20 – 50 nM. Brain exposure of the compound was tested in mice with radioactivity of [¹⁴C]DS-1001a, and the results suggested DS-1001a penetrates blood-brain barrier (BBB). Administration of DS-1001b showed great reduction of 2-HG in the tumor and clear anti-tumor effects against subcutaneous A1074 PDX model with heterozygous IDH1R132H.

Conclusions

Our results indicate that DS-1001b, which is currently in a phase I clinical trial for treating glioma with IDH1 mutations (NCT03030066), is BBB-permeable and effective against the PDX model of IDH1 mutant glioma through inhibition of IDH1 mutant proteins.

Clinical trial identification

NCT03030066.

Editorial acknowledgement

Legal entity responsible for the study

Daiichi Sankyo Co., Ltd.

Funding

Daiichi Sankyo Co., Ltd.

Disclosure

H. Matsunaga: Full / Part-time employment: Daiichi Sankyo Co., Ltd. Y. Machida: Research grant / Funding (institution): Daiichi Sankyo Co., Ltd. M. Nakagawa: Research grant / Funding (institution): Daiichi Sankyo Co., Ltd. M. Yamaguchi: Research grant / Funding (institution): Daiichi Sankyo Co., Ltd. Y. Ogawara: Research grant / Funding (institution): Daiichi Sankyo Co., Ltd. Y. Shima: Research grant / Funding (institution): Daiichi Sankyo Co., Ltd. K. Yamagata: Research grant / Funding (institution): Daiichi Sankyo Co., Ltd. T. Katsumoto: Research grant / Funding (institution): Daiichi Sankyo Co., Ltd. A. Hattori: Research grant / Funding (institution): Daiichi Sankyo Co., Ltd. M. Itoh: Full / Part-time employment: Daiichi Sankyo Co., Ltd. T. Seki: Full / Part-time employment: Daiichi Sankyo Co., Ltd. Y. Nishiya: Full / Part-time employment: Daiichi Sankyo Co., Ltd. K. Nakamura: Full / Part-time employment: Daiichi Sankyo Co., Ltd. K. Suzuki: Full / Part-time employment: Daiichi Sankyo Co., Ltd. T. Imaoka: Full / Part-time employment: Daiichi Sankyo Co., Ltd. M. Suzuki: Full / Part-time employment: Daiichi Sankyo RD Novare Co., Ltd. K. Ichimura: Research grant / Funding (institution): Daiichi Sankyo. I. Kitabayashi: Research grant / Funding (institution): Daiichi Sankyo Co., Ltd. All other authors have declared no conflicts of interest.