Table 1.

Biochemical, cellular and pharmacokinetic (PK) properties of mIDH-selective inhibitors.

Compound	Biochemical IC50	Cellular IC50	Preclinical PK Properties
ML309 [60,70]	IDH1R132H: 96–335 nm IDH1R132C: 62–622 nm a IDH1WT: 21–36 µm IDH2R172Q: >30 µm IDH2WT: >30 µm	IDH1R132H: 150–248 nm IDH1R132S: 970 nm IDH1R132G: 711 nm IDH1R132C: 541–623 nm	-microsomal t1/2: 1–3 min -PAMPA Papp: >170 × 10−5 cm/s -ERCaco-2: 2.9 -fu,plasma: 0.01 -plasma t1/2: >3 h -no brain penetration
AG-135 [60,65]	IDH1R132H: 42–375 nm IDH1R132H/WT: 80 nm b IDH1R132C: 4–182 nm a IDH1WT: 2–15 µm IDH2R172K: >10 µm IDH2R172Q: >30 µm IDH2R140Q: >10 µm IDH2WT: >10–30 µm	IDH1R132H: 81–217 nm IDH1R132S: 810 nm IDH1R132G: 681 nm IDH1R132C: 480–530 nm	-microsomal t1/2: 1.5–2.7 min -PAMPA Papp: 79 × 10−5 cm/s -ERCaco-2: 13 -fu,plasma: 0.01
AGI-5198 [60,64,71,72,73,74]	IDH1R132H: 17–385 nm IDH1R132C: 0.2–13.3 µm a IDH1WT: >30–100 µm IDH2R140Q: >100 µm IDH2R172Q: >30 µm IDH2R172K: >100 µm IDH2WT: >30–100 µm	IDH1R132H: 43–70 nm IDH1R132S: 2 µm IDH1R132G: 1.6 µm IDH1R132C: 0.5–1.5 µm	-microsomal t1/2: 3–4 min -PAMPA Papp: >140 × 10−5 cm/s -ERCaco-2: 23.1 -fu,plasma: 0.03–0.04 -no brain penetration
AG-120 (Ivosidenib) [60,73,75]	IDH1R132H: 12–40 nm IDH1R132H/WT: 5–12 nm b IDH1R132C: 13–205 nm a IDH1R132G: 8 nm IDH1R132L: 13 nm IDH1R132S: 12 nm IDH1WT: 0.024–4.3 µm IDH2R172Q: >30 µm IDH2WT: >30 µm	IDH1R132H: 19–50 nm IDH1R132S: 12–220 nm IDH1R132G: 16 nm IDH1R132C: 8–46 nm	-microsomal t1/2: >120 min -Clint(in vivo): 9 mL/min/kg -PAMPA Papp: 54 × 10−5 cm/s -ERCaco-2: 2.0–56.4 -ERMDR1-MDCK: >350 -fu,plasma: 0.09 -Kp,brain: 0.04 -plasma t1/2: 2.5–19 h
IDH889 [76]	IDH1R132H: 20 nm IDH1R132C: 72 nm IDH1WT: 1.38 µm	IDH1R132H: 14 nm	-Clint(in vitro): 143–588 µL/min/mg -fu,plasma: 0.01–0.03 -Kp,brain: 1.4
IDH305 [75,77,78]	IDH1R132H: 27–50 nm IDH1R132C: 28–50 nm IDH1WT: 6.14 µm	IDH1R132H: 24 nm IDH1R132C: 53 nm IDH2R140Q: 3.8 µm IDH2R172K: 10 µm	-Clint(in vitro): 28–61 µL/min/mg -Clint(in vivo): 24–34 mL/min/kg -ERCaco-2: 1.2 -fu,plasma: 0.11–0.17 -fu,brain: 0.05–0.07 -Kp,brain: 0.29–0.61 -Kp,uu,brain: 0.17–0.18
Novartis 224 [60,79]	IDH1R132H: 17–130 nm IDH1R132C: 84–552 nm a IDH1WT: 3.9 µm IDH2R172Q: >30 µm IDH2WT: >30 µm	IDH1R132H: 52–92 nm IDH1R132S: 221 nm IDH1R132G: 121 nm IDH1R132C: 83–195 nm	-microsomal t1/2: 1–2 min -PAMPA Papp: 156 × 10−5 cm/s -ERCaco-2: 1.7 -fu,plasma: 0.01
Novartis 530 [60,79]	IDH1R132H: 8.3–51 nm IDH1R132C: 32–98 nm a IDH1WT: 3.5 µm IDH2R172Q: >30 µm IDH2WT: >30 µm	IDH1R132H: 34–54 nm IDH1R132S: 78 nm IDH1R132G: 76 nm IDH1R132C: 49–52 nm	-microsomal t1/2: 1–3 min -PAMPA Papp: 98 × 10−5 cm/s -ERCaco-2: 1.1 -fu,plasma: 0.02
Novartis 556 [60,79]	IDH1R132H: <72–141 nm IDH1R132C: 189–875 nm a IDH1WT: 10.5 µm IDH2R172Q: >30 µm IDH2WT: >30 µm	IDH1R132H: 186–334 nm IDH1R132S: 912 nm IDH1R132G: 1.1 µm IDH1R132C: 582 nm IDH1R132C: 686 nm	-microsomal t1/2: 8–24 min -PAMPA Papp: 39 × 10−5 cm/s -ERCaco-2: 2.6 -fu,plasma: 0.14
2 (see Section 7.2) [75]	IDH1R132H: 4.0 nm IDH1R132C: 8.2 nm	IDH1R132C: 15.9 nm	-Clint(in vivo): 23 mL/min/kg -plasma t1/2: 1.5–2.5 h
BAY1436032 [44,80,81,82]	IDH1R132H: 15 nm IDH1R132C: 15 nm IDH1WT: 20 µm IDH2WT: >100 µm	IDH1R132H: 5–73 nm IDH1R132C: 5–135 nm IDH1R132G: 4 nm IDH1R132L: 3 nm IDH1R132S: 16 nm	-Clint(in vivo): 2.5 mL/min/kg -plasma t1/2: 3.1 h -Kp,brain: 0.08–0.38 -ERCaco-2: 0.17
4 (see Section 7.4) [83]	IDH1R132H: 127 nm IDH1R132C: 2.25 µm IDH1WT: 100 µm	IDH1R132H: 266–316 nm IDH1R132C: 1.2–1.9 µm	-microsomal t1/2: <30 min -plasma t1/2: 1.27 h
5 (see Section 7.4) [83]	IDH1R132H: 18 nm IDH1R132C: 130 nm IDH1WT: 35 µm IDH2R140Q: 76.6 µm IDH2R172K: 33.8 µm	IDH1R132H: 18–45 nm IDH1R132C: 130–233 nm IDH1R132G: 120 nm IDH1R132L: 60 nm IDH1R132S: 1.5 µm	-Clint(in vitro): 7.0 µL/min/mg -Clint(in vivo): 3.3–8.6 mL/min/kg -plasma t1/2: 2.2–10.0 h -PAMPA Papp: 180 × 10−5 cm/s -ERCaco-2: 1.0 -ERMDR1-MDCK: 1.19 -fu,plasma: 0.02–0.04
6 (see Section 7.4) [83]	IDH1R132H: 9 nm IDH1R132C: 36 nm	IDH1R132H: 1–11 nm IDH1R132C: 4–40 nm IDH1R132G: 3 nm IDH1R132L: 5 nm IDH1R132S: 129 nm	-Clint(in vitro): 7.0–10.1 µL/min/mg -Clint(in vivo): 4.3–16.4 mL/min/kg -plasma t1/2: 2.6–6.2 h -PAMPA Papp: 127 × 10−5 cm/s -ERCaco-2: 1.65 -fu,plasma: 0.01–0.02
FT-2102 (Olutasidenib) [84,85]	IDH1R132H: 4.9–21 nm IDH1R132C: 114–178 nm IDH1WT: 22.4–>100 µm IDH2R140Q: >100 µm IDH2R172K: 27.3 µm IDH2WT: >100 µm	IDH1R132H: 9–21 nm IDH1R132C: 39–94 nm IDH1R132L: 42 nm IDH1R132G: 6 nm IDH1R132S: 9 nm	-PAMPA Papp: 199 × 10−5 cm/s -ERCaco-2: 1.35 -Kp,brain: 0.24–0.38
GSK321 [86]	IDH1R132H: 4.6 nm IDH1R132C: 3.8 nm IDH1R132G: 2.9 nm IDH1WT: 46 nm IDH2R140Q: 1.4 µm IDH2R172S: 1.0 µm IDH2WT: 496 nm	IDH1R132C: 85 nm	-ERCaco-2: 1.4
GSK864 [60,86]	IDH1R132H: 15–162 nm IDH1R132C: 8.8–668 nm a IDH1R132G: 16.6 nm IDH1WT: 0.5–2.7 µm IDH2R140Q: 1.9 µm IDH2R172Q: 22 nm IDH2R172S: 997 nm IDH2WT: >30 µm	IDH1R132H: 120–191 nm IDH1R132S: 532 nm IDH1R132G: 519 nm IDH1R132C: 299–341 nm	-microsomal t1/2: 13–73 min -PAMPA Papp: 36 × 10−5 cm/s -ERCaco-2: 1.3–5.1 -fu,plasma: 0.01
AG-221 (Enasidenib) [60,87,88]	IDH1R132H: 5–>30 µm IDH1R132H/WT: 677 nm b IDH1R132C: 13–>30 µm a IDH1WT: 0.5–15.1 µm IDH2R140Q: 9–100 nm IDH2R140Q/WT: 40–380 nm b IDH2R172Q: 44 nm IDH2R172K: 200–400 nm IDH2R172K/WT: 30–180 nm b IDH2WT: 18–>30 µm	IDH2R140Q: 10–20 nm IDH2R172K: 0.5–1.6 µm	-microsomal t1/2: >120 min -Clint(in vivo): 13.8 mL/min/kg -PAMPA Papp: 131 × 10−5 cm/s -plasma t1/2: 5.4 h -ERCaco-2: 2.5 -fu,plasma: 0.01 -Kp,brain: 0.14
IDH2-C100 [60,88]	IDH1R132H: 9.4 µm IDH1R132C: 16–>30 µm a IDH1WT: >30 µm IDH2R140Q: 7 nm IDH2R172Q: 343 nm IDH2WT: 6.6 µm	IDH2R140Q: 30 nm	-microsomal t1/2: 13–27 min -PAMPA Papp: 48 × 10−5 cm/s -ERCaco-2: 4.1 -fu,plasma: <0.01
AG-881 (Vorasidenib) [87]	IDH1R132H: 6–8 nm IDH1R132H/WT: 0.6–4 nm b IDH1R132C: 19 nm IDH1R132G: 17 nm IDH1R132L: 34 nm IDH1R132S: 6 nm IDH1WT: 4–190 nm IDH2R140Q: 12–118 nm IDH2R140Q/WT: 32–251 nm b IDH2R172K: 32–94 nm IDH2R172K/WT: 8–49 nm b IDH2WT: 31–374 nm	IDH1R132H: 3–3.2 nm IDH1R132C: 3.8–22 nm IDH1R132S: 0.8 nm IDH1R132G: 6.6 nm IDH2R140Q: 7.1–14 nm IDH2R172K: 130 nm	-Kp,brain: 0.62–1.96
AGI-12026 [87]	IDH1R132H: 78 nm IDH1R132H/WT: 20 nm b IDH2R140Q: 19 nm		-Kp,brain: 2.5
AGI-15056 [87]	IDH1R132H: 48 nm IDH1R132H/WT: 6 nm b IDH2R140Q: 22 nm	IDH1R132H: 2 nm IDH2R140Q: 14 nm	-Kp,brain: 1.5

^a Upper limit determined with very high (5 mm) α-KG concentration; ^b determined with the respective mutant and wildtype IDH heterodimers. Abbreviations: microsomal t_1/2—in vitro metabolic stability determined as half-life in liver microsomes; Cl_{int(in vitro)}—in vitro metabolic stability determined as intrinsic clearance in hepatocytes or liver microsomes; Cl_{int(in vivo)}—in vivo metabolic stability determined as intrinsic clearance in pharmacokinetic studies; plasma t_1/2—in vivo half-life in blood determined in pharmacokinetic studies; PAMPA P_app—apparent permeability coefficient determined in parallel artificial membrane permeability assays (PAMPA); ER_Caco-2—efflux ratio determined in Caco-2 cells; ER_MDR1-MDCK—efflux ratio determined in MDCK cells transfected with the efflux transporter P-gp; f_u,plasma—unbound fraction of drug in plasma; f_u,brain—unbound fraction of drug in brain; K_p,brain—concentration ratio of total drug in brain and blood; K_p,uu,brain—concentration ratio of unbound drug in brain and blood.