Hu7691 free base

Hu7691 free base is an orally active, selective Akt inhibitor with IC50s of 4.0 nM, 97.5 nM, 28 nM for Akt1, Akt2 and Akt3, respectively. Hu7691 free base inhibits tumor growth and enables decrease of cutaneous toxicity in mice[1].

Signaling Pathways >> Epigenetics >> PKC

Research Areas >> Cancer

Signaling Pathways >> Metabolic Enzyme/Protease >> SGK

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> PKA

Signaling Pathways >> Stem Cell/Wnt >> PKA

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

Signaling Pathways >> PI3K/Akt/mTOR >> Akt

Signaling Pathways >> MAPK/ERK Pathway >> Ribosomal S6 Kinase (RSK)

Signaling Pathways >> TGF-beta/Smad >> PKC

Signaling Pathways >> Stem Cell/Wnt >> ROCK

Signaling Pathways >> TGF-beta/Smad >> ROCK

Akt1:4.0 nM (IC50)

Akt2:97.5 nM (IC50)

Akt3:28 nM (IC50)

PKA:11 nM (IC50)

PKCη:629 nM (IC50)

ROCK1:354 nM (IC50)

RSK1:756 nM (IC50)

p70S6K:229 nM (IC50)

Hu7691 free base displays low inhibitions against most of the kinases in the four families (AGC, TK, TKL, Lipid/Atypical; PKA, IC50=11 nM; PKCη, IC50=629 nM; ROCK1, IC50=354 nM; RSK1, IC50=756 nM; P70S6K, IC50=229 nM; SGK, IC50=1009 nM)[1]. Hu7691 free base (2.25-36 μM; 24 hours) induces effective decrease of the phosphorylation level of Akt (S473)[1]. Hu7691 free base (10, 20, 30, 40 μM; for 72 h) exhibits low toxicity against HaCaT cells with an IC50 value of 15.2 μM[1]. Hu7691 free base has a significant inhibitory effect on the growth of 18 kinds of human tumor cells (U87-MG, U251, A549, HepG2, HT-29, KHOS, MDA-MB-231, PC3, SKOV3 and so on) derived from different tissues, with the IC50 range of 0.6-27 μM. Hu7691 free base shows low antiproliferation activities against the HL7702 and HPDE6-C7 normal cells, exhibiting IC50 values of 5.4 and 16.1 μM, respectively[1]. Western Blot Analysis[1] Cell Line: HaCaT cells Concentration: 2.25, 4.5, 9, 18, 36 μM Incubation Time: 24 hours Result: Induced effective decrease of the phosphorylation level of Akt (S473).

Hu7691 free base (12.5-50 mg/kg/day; i.g.; for 22 days) shows dose-dependent tumor growth inhibition[1]. Hu7691 free base (15 mg/kg; oral) has a T1/2 of 8.68 hours, a Cmax of 171.17 ng/mL and an AUC of 2820.64 ng/mL•h in rats[1]. Hu7691 free base (2 mg/kg; iv) has a T1/2 of 6.24 hours, a Cmax of 207.52 ng/mL and an AUC of 532.87 ng/mL•h in rats[1]. Hu7691 free base (20 mg/kg; oral) has a T1/2 of 16.7 hours, a Cmax of 905.65 ng/mL and an AUC of 36303 ng/mL•h in beagle dog (male, 40 weeks old, 8–10 kg)[1]. Animal Model: Balb/c mice (nu/nu, female, 3-4 weeks old, 20-25 g) with 786-O and KHOS xenograft[1] Dosage: 12.5, 25, 50 mg/kg Administration: Oral; once daily for 22 days Result: Showed dose-dependent tumor growth inhibition. Animal Model: SD rats (male, 8 weeks old, 250-300 g)[1] Dosage: 15 mg/kg (Pharmacokinetic Analysis) Administration: Oral Result: Had a T1/2 of 8.68 hours, a Cmax of 171.17 ng/mL and an AUC of 2820.64 ng/mL•h.

[1]. Jinxin Che, et al. Discovery of N-((3 S,4 S)-4-(3,4-Difluorophenyl)piperidin-3-yl)-2-fluoro-4-(1-methyl-1 H-pyrazol-5-yl)benzamide (Hu7691), a Potent and Selective Akt Inhibitor That Enables Decrease of Cutaneous Toxicity. J Med Chem. 2021 Aug 26;64(16):12163-12180.