Agi 5198

Detailed lists of all 128 compounds included in the epigenetics compound library (L1900, Selleckchem, Houston, TX, USA) and of all twenty compounds included in the custom designed compound library for the HDAC inhibitor combination drug screen are available in the Supplementary Files (Table S3 and Table S4, respectively). The IDH1 mutant (R132H and R132C) inhibitor AGI-5198 (14624, Cayman Chemical, Ann Arbor, MI, USA), the cell permeable derivative of D-2-HG ((2R)-Octyl-α-hydroxyglutarate, 16366, Cayman Chemical), the HDAC inhibitor romidepsin (S3020, Selleckchem), the glutamate dehydrogenase inhibitor chloroquine diphosphate (S4157, Selleckchem), the glutaminase inhibitor metformin HCl (S1950, Selleckchem) and the B-cell lymphoma 2 (Bcl-2) family member inhibitors ABT-737 (Bcl-2/Bcl-xL/Bcl-w, S1002, Selleckchem), S63845 (Mcl-1, S8383, Selleckchem), venetoclax (Bcl-2, S8048, Selleckchem), and WEHI-539 (Bcl-xL, A3935, APExBIO, Houston, TX, USA) were dissolved in DMSO, PBS, or RPMI 1640 medium according to the manufacturer’s protocol.

The PARP inhibitor talazoparib (S7048, Selleckchem, Houston, TX, USA), the IDH1 mutant (R132H and R132C) inhibitor AGI-5198 (14624, Cayman Chemical, Ann Arbor, MI, USA), the alkylating agent temozolomide (S1237, Selleckchem) and the Bcl-xL/Bcl-2/Bcl-w inhibitor ABT-737 (S1002, Selleckchem) were dissolved in DMSO. The cell permeable derivative of D-2-HG, (2R)-Octyl-α-hydroxyglutarate (16366, Cayman Chemical), was dissolved in phosphate buffered saline (PBS). Doxorubicin (2 mg/mL in 0.9% NaCl) and cisplatin (1 mg/mL in 0.9% NaCl) were obtained from Leiden University Medical Center (in-house hospital pharmacy) and diluted in PBS. Hydrogen peroxide (H₂O₂) (Merck, Darmstadt, Germany) was also diluted in PBS.

Novartis 224 (HY-18717), Novartis 556 (HY-13972), Agios 135 (HY-12475), and AG-221 (HY-18690) were purchased from Medchem Express. AGI-5198 (14624) and AGI-6780 (14639) were purchased from Cayman Chemicals. IDH2-C100 was purchased from XcessBio. AG-120 was purchased from CG Biopharma. GSK864 was a gift from Structure Genomics Consortium^{24 (link)}. ML309 was synthesized as previously described^{20 (link)}. The synthesis of Sanofi 1 and Novartis 530 are reported in the supplemental methods.

All liquid chromatography solvents and additives were obtained from Sigma-Aldrich (St. Louis, MO) and Honeywell Burdick & Jackson (Morris-town, NJ). All cell culture media and reagents were purchased from Thermo Fisher (Mountain View, CA) or Sciencell (Carlsbad, CA). H₂O₂ was purchased from Sigma-Aldrich (St. Louis, MO). Human colorectal carcinoma (HCT116) cells with a heterozygous knockin of IDH1 mutant (R132H) were obtained from Horizon Discovery (Cambridge, UK). Human immortalized astrocytes were generated as described below. All stable isotopes were purchased from Cambridge Isotope Laboratories (Tewksbury, MO). AGI-5198 was purchased from Cayman Chemical (Ann Arbor, MI). Palmitate-BSA conjugate was purchased from Seahorse Bioscience (Santa Clara, CA).