HDAC-IN-31

HDAC-IN-31 is a potent, selective and orally active HDAC inhibitor with IC50s of 84.90, 168.0, 442.7, >10000 nM for HDAC1, HDAC2, HDAC3, HDAC8, respectively. HDAC-IN-31 induces apoptosis and cell cycle arrests at G2/M phase. HDAC-IN-31 shows good antitumor efficacy. HDAC-IN-31 has the potential for the research of diffuse large B-cell lymphoma[1].

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> Cell Cycle/DNA Damage >> HDAC

Signaling Pathways >> Epigenetics >> HDAC

HDAC1:84.90 nM (IC50)

HDAC2:168.0 nM (IC50)

HDAC3:442.7 nM (IC50)

HDAC8:>10000 nM (IC50)

HDAC-IN-31 (compound 24g) (2 µM) shows growth-inhibitory activities with the inhibition rate of 2.32%, 44.01%, 48.53%, 64.94% for TMD-8, HCT 116, A549, MDA-MB-231 cells[1]. HDAC-IN-31 (1 µM) shows selectivity with the IC50s of 84.9, 168.0, 442.7, >10000 nM for HDAC 1, HDAC 2, HDAC 3, HDAC 8, and 81.20%, 84.43%, 88.07%, 92.34%, 96.88%, 91.98% enzyme activity for HDAC4, HDAC 5,HDAC 7, HDAC9, HDAC 6, HDAC 11, respectively[1]. HDAC-IN-31 (2.5, 5, 7.5, 10 µM; 24 h) increases the expression of HDAC1, Ace-H3, Ace-H4, Cleaved PARP, Cleaved Caspase-3 in a dose-dependent manner[1]. HDAC-IN-31 (0-4 µM; 24 h)induce apoptosis and cell cycle arrests in G2/M phase in a dose-dependent manner[1]. Cell Proliferation Assay[1] Cell Line: MDA-MB-231, A549, NCI-H460, HCT-116,SK-OV-3, HT-29, COLO 678, NCI-H441, 22Rv1, 786-O, TMD-8, DOHH-2, CCRF-CEM, SU-DHL-2, REC-1, MOLT-4, HUT-78, RS4;11 cells Concentration: 0-20 µM Incubation Time: 72 h Result: Showed a broad spectrum of antitumor activity with the IC50s of 2.29, 2.85, 1.58, 1.16, 3.17, 2.41, 8.02, 2.62, 1.14, 0.60, 0.31, 0.39, 0.48, 0.51, 0.33, 0.38, 0.80, 0.47 µM for MDA-MB-231, A549, NCI-H460, HCT-116, SK-OV-3, HT-29, COLO 678, NCI-H441, 22Rv1, 786-O, TMD-8, DOHH-2, CCRF-CEM, SU-DHL-2, REC-1, MOLT-4, HUT-78, RS4;11 cells, respectively. Western Blot Analysis[1] Cell Line: TMD-8 cells Concentration: 2.5, 5, 7.5, 10 µM Incubation Time: 24 h Result: Promoted the HDAC1, HDAC2, HDAC3 substrate Ace-H3 and Ace-H4 acetylation with a dose-dependent manner. Apoptosis Analysis[1] Cell Line: TMD-8 cells Concentration: 0.5, 1, 2, 4 µM Incubation Time: 24 h Result: Induced cell apoptosis at a concentration-dependent manner. Cell Cycle Analysis[1] Cell Line: TMD-8 cells Concentration: 250, 500, 1000 nM Incubation Time: 24 h Result: Arrested the cell cycle at G2/M phase in a dose-dependent manner.

HDAC-IN-31 (2 mg/kg for i.v.; 10, 100 mg/kg for p.o.) shows good bioavailability with a significant dose dependent manner[1]. HDAC-IN-31 (50, 100 mg/kg; p.o, daily for 21 consecutive days) shows good antitumor efficacy in a TMD-8 xenograft model without obvious toxicity[1]. Pharmacokinetic Parameters of HDAC-IN-31 in mice[1]. Parameters Unit 24 g (25 mg/kg) Cmax ng·h·mL-1 3100±231 T1/2(po) h 4.4±0.3 AUC0-inf(iv) ng·h·mL-1 1040±142 AUC0-inf(po) ng·h·mL-1 5180±252 MRTPO h 2.6±0.4 F % 39.9±2.1ICR mouse; 2 mg/kg for i.v.; 25 mg/kg for p.o.[1]. Pharmacokinetic Parameters of HDAC-IN-31 in tumor models[1]. Parameters Unit po (25 mg/kg) po (50 mg/kg) po (100 mg/kg) Cmax ng·h·mL-1 1700±317 14700±1024 10700±1001 AUC0-t ng·h·mL-1 1220±242 9710±314 9740±230 AUC0-inf ng·h·mL-1 1230±165 9730±341 9770±332 MRT0-t h 0.750±0.043 0.812±0.023 1.43±0.56 MRT0-inf h 0.805±0.086 0.821±0.041 1.51±0.32Mouse; 25, 50, 100 mg/kg for p.o.[1]. Pharmacokinetic Parameters of HDAC-IN-31 in tumor models[1]. PK parameters Unit iv (2 mg/kg) po (10 mg/kg) po (100 mg/kg) Cmax ng·h·mL-1 3960±413 58300±1352 T1/2 h 0.427±0.016 1.31±0.27 1.63±0.52 AUC0-inf ng·h·mL-1 1250±132 2670±286 57200±1047 MRT h 0.402±0.032 0.919±0.052 0.897±0.041 CL mL·kg·min-1 27.2±1.2 F % 45.6±1.2 91.8±2.3ICR mice; 2 mg/kg for i.v.; 10, 100 mg/kg for p.o.[1]. Pharmacokinetic Parameters of HDAC-IN-31 in tumor models[1]. PK parameters Unit Monkey Dog iv (1 mg/kg) po (10 mg/kg) iv (1 mg/kg) po (10 mg/kg) Cmax ng·h·mL-1 8520±301 4740±243 T1/2 h 4.31±0.56 9.14±0.32 1.65±0.41 1.51±0.33 AUC0-inf ng·h·mL-1 15700±1842 53200±1241 2550±365 15100±2004 MRT h 3.41±0.12 8.28±0.32 2.26±0.41 2.71±0.32 CL mL·kg·min-1 1.35±0.21 6.72±0.35 Vdss L·kg-1 0.34±0.22 0.55±0.04 F % 27.6±2.1 58.9±1.2Dogs and monkeys; 1 mg/kg for i.v., 10 mg/kg for p.o. for monkey; 1 mg/kg for i.v., 10 mg/kg for p.o. for dog[1]. Animal Model: ICR mice[1] Dosage: 2 mg/kg for i.v.; 25 mg/kg for p.o.(DMSO/PEG200/saline = 20:20:60, v/v/v) Administration: I.v. or p.o. Result: Showed high oral bioavailability (F=40%). Animal Model: Mouse[1] Dosage: 25, 50, 100 mg/kg Administration: P.o. Result: Did not exhibit a significant dose dependent for oral administration. Animal Model: ICR mice[1] Dosage: 2, 10, 100 mg/kg (into the form of hydrochloride) Administration: 2 mg/kg for i.v.; 10, 100 mg/kg for p.o. Result: Showed good bioavailability with a significant dose dependent. Animal Model: Dogs and monkeys[1] Dosage: 1, 10 mg/kg Administration: 1 mg/kg for i.v.; 10 mg/kg for p.o. Result: Showed good pharmacokinetic characteristics for different species. Animal Model: 5-6 weeks, female CB.17 SCID mice (TMD-8 tumor xenografts)[1] Dosage: 50, 100 mg/kg Administration: P.o, daily for 21 consecutive days Result: Inhibited the tumor growth with the inhibition rate of 77% and had no significant effect on the internal organs of mice at 100 mg/kg/d.

[1]. Cui H,et al. Design and synthesis of HDAC inhibitors to enhance the therapeutic effect of diffuse large B-cell lymphoma by improving metabolic stability and pharmacokinetic characteristics. Eur J Med Chem. 2022 Feb 5;229:114049.