Safusidenib

Safusidenib is an orally bioavailable, selective mutant IDH1 inhibitor. Safusidenib strongly inhibits mutant IDH1 but not wild-type IDH1. Safusidenib impairs tumor activity in chondrosarcoma[1]. Safusidenib exhibits activity against IDH1R132H, and IDH1R132C with IC50s of 15, and 130 nM in assays without any preincubation, respectively[2].

Research Areas >> Cancer

Signaling Pathways >> Metabolic Enzyme/Protease >> Isocitrate Dehydrogenase (IDH)

Safusidenib (DS-1001b) impairs the proliferation of IDH1-mutated chondrosarcoma cell lines and decreases 2-HG levels[1]. Safusidenib impairs the proliferation of IDH1 mutant chondrosarcoma cell lines in a dose-dependent manner, whereas Safusidenib has little effect on the proliferation of the IDH wild-type cell lines OUMS27 and NDCS-1; GI50 values for JJ012, L835, OUMS27, and NDCS-1 cells are 81 nM (day 14), 77 nM (6 weeks), >10 μM (day 10), and >10 μM (day 10), respectively[1]. Safusidenib (1, and 10 μM; for 6 weeks) markedly upregulates SOX9, a key regulator of chondrocyte differentiation, at the protein level[1]. Safusidenib (1 μM) significantly upregulates CDKN1C at the protein level[1]. Safusidenib (DS-1001b) exhibits activity against IDH1 or IDH2 enzymes with IC50s of 8.4, 11, and 180 nM for IDH1R132H, IDH1R132C, and IDH1WT in assays conducted with a 2-hour preincubation step[2]. Cell Proliferation Assay[1] Cell Line: The IDH1 mutant cell lines JJ012 and L835 cells Concentration: 0.1, 1, and 10 μM Incubation Time: 0, 3, 6, 9, 12, and 15 days Result: Impaired proliferation in both cell lines in a dose-dependent manner. Western Blot Analysis[1] Cell Line: L835 cells Concentration: 0, 1, and 10 μM Incubation Time: 6 weeks Result: Markedly upregulated SOX9 at the protein level.

Safusidenib (DS-1001b) has antineoplastic activity in JJ012 xenografts. Continuous administration of Safusidenib (mixed with sterilized pellet food and fed continuously for 6 weeks) impairs tumor growth in xenograft mice[1]. Animal Model: NOD-SCID bearing JJ012 xenograft[3] Dosage: Mixed with sterilized pellet food (CRF-1; Oriental Yeast) and fed ad libitum for 6 weeks.Mixed with sterilized pellet food (CRF-1; Oriental Yeast) and fed ad libitum for 6 weeks. Administration: Fed continuously starting at 3 weeks Result: Continuous administration significantly impaired tumor growth in JJ012 xenograft mice.

[1]. Makoto Nakagawa, et al. Selective inhibition of mutant IDH1 by DS-1001b ameliorates aberrant histone modifications and impairs tumor activity in chondrosarcoma. Oncogene. 2019 Oct;38(42):6835-6849.

[2]. Yukino Machida, et al. A Potent Blood-Brain Barrier-Permeable Mutant IDH1 Inhibitor Suppresses the Growth of Glioblastoma with IDH1 Mutation in a Patient-Derived Orthotopic Xenograft Model. Mol Cancer Ther. 2020 Feb;19(2):375-383.