Onalespib Chemical Properties

Boiling point:

605.7±55.0 °C(Predicted)

Density 

1.237

storage temp. 

Store at -20°C

solubility 

insoluble in H2O; ≥13.25 mg/mL in DMSO; ≥47.7 mg/mL in EtOH with ultrasonic

form 

solid

pka

8.50±0.48(Predicted)

color 

White to off-white

InChI

InChI=1S/C24H31N3O3/c1-16(2)20-11-21(23(29)12-22(20)28)24(30)27-14-18-5-4-17(10-19(18)15-27)13-26-8-6-25(3)7-9-26/h4-5,10-12,16,28-29H,6-9,13-15H2,1-3H3

InChIKey

IFRGXKKQHBVPCQ-UHFFFAOYSA-N

SMILES

C(N1CC2=C(C1)C=CC(CN1CCN(C)CC1)=C2)(C1=CC(C(C)C)=C(O)C=C1O)=O

Onalespib Usage And Synthesis

Description

Onalespib, also known as AT13387, is a selective inhibitor of Hsp90 (IC50 = 18 nM). It induces the degradation of specific Hsp90 client proteins, including mutant EGFR, for up to seven days in tumor cell lines in vitro and up to three days in vivo. Onalespib is retained in tumor xenografts and is efficacious in a range of xenograft models. It differs from other HSP90 inhibitors in its longer duration of target inhibition and its favorable toxicity profile in phase I studies in patients with refractory solid tumors.

Definition

ChEBI: Onalespib is a member of the class of isoindoles that is isoindole in which the amino group has been acylated by a 2,4-dihydroxy-5-isopropylbenzoyl group and in which position 5 of the isoidole moiety has been substituted by a (4-methylpiperazin-1-yl)methyl group. A second-generation Hsp90 inhibitor. It has a role as a Hsp90 inhibitor and an antineoplastic agent. It is a member of resorcinols, a member of benzamides, a tertiary carboxamide, a member of isoindoles and a N-alkylpiperazine.

Synthesis

The product of step 11 (0.9 kg, 1.53 mol) was dissolved in a solvent mixture of isopropanol (6.8 L) and water (1.04 L). 10% Pd/C catalyst (90 g) and potassium carbonate (0.212 kg, 1.53 mol) were added to the solution under nitrogen protection. Subsequently, the suspension was hydrogenated for 60 to 70 min under hydrogen pressure of 3 bar. After completion of the reaction, the reaction mixture was diluted with water (0.5 L) and filtered. A 30% aqueous hydrochloric acid solution (0.85 kg, diluted with 5.42 kg of water) was added to the filtrate and then concentrated under vacuum at 60 °C to remove 10 L of isopropanol. Water (0.45 L) was added to the concentrated solution and concentration was continued until another 10 L of isopropanol was removed. The organic phase was extracted with water (4.61 L) and then diluted with acetonitrile (4.06 L). The pH was adjusted to 7.5-8.5 by dropwise addition of concentrated aqueous ammonia solution (0.35 kg). the resulting suspension was stirred for 2.5 h, followed by filtration to remove the solids. The residue was washed with acetonitrile (2 x 0.8 L) and dried to constant weight at 40 °C to give a final product of (2,4-dihydroxy-5-isopropylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone 588 g in 94% yield.

target

Hsp90

Mode of action

Onalespib selectively binds to Hsp90, thereby inhibiting its chaperone function and promoting the degradation of oncogenic signaling proteins involved in tumor cell proliferation and survival. Hsp90, a chaperone protein upregulated in a variety of tumor cells, regulates the folding, stability and degradation of many oncogenic signaling proteins and has been used as a biomarker of HSP90 inhibition.

References

Efficacy of Onalespib, a Long-Acting Second-Generation HSP90 Inhibitor, as a Single Agent and in Combination with Temozolomide against Malignant Gliomas
https://pubchem.ncbi.nlm.nih.gov/compound/Onalespib

Onalespib(912999-49-6)Related Product Information

• Bortezomib
• BIIB-021
• 4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)-2-((1r,4r)-4-hydroxycyclohexylamino)benzamide
• PU-H71
• Flavopiridol (Alvocidib) HCl
• Ganetespib