AT13387

Names

[ Name ]:
AT13387

[Synonym ]:
UNII-Q7Y33N57ZZ
(2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl]-methanone
AT-13387
Methanone, [1,3-dihydro-5-[(4-methyl-1-piperazinyl)methyl]-2H-isoindol-2-yl][2,4-dihydroxy-5-(1-methylethyl)phenyl]-
AT13387
2-(2,4-dihydroxy-5-isopropylbenzoyl)-5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindole
CS-0969
N-(2,4-dihydroxy-5-iso-propylbenzoyl)(5-(4-methylpiperazin-1-yl)methyl)-iso-indoline
(2,4-Dihydroxy-5-isopropylphenyl){5-[(4-methyl-1-piperazinyl)methyl]-1,3-dihydro-2H-isoindol-2-yl}methanone
Onalespib

Biological Activity

[Description]:

Onalespib (AT13387) is a potent inhibitor of Hsp90, with a Kd of 0.71 nM.

[Related Catalog]:

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

Signaling Pathways >> Metabolic Enzyme/Protease >> HSP

Research Areas >> Cancer

[Target]

HSP90:0.71 nM (Kd)

[In Vitro]

Onalespib (Compound 35) is a potent inhibitor of Hsp90, with Kd of 0.71 nM. Onalespib shows potent antiproliferative activity in HCT116 cells, with an IC50 of 31 nM. Onalespib also strongly inhibits the proliferation of a panel of human tumor cell lines, showing IC50 of < 100 nM[1]. Onalespib exhibits cytotoxic activity against many of the PPTP cell lines, with median IC50 of 41 nM[2].

[In Vivo]

Onalespib (60 mg/kg, ip 3 days on and 3 days off for four cycles) shows antitumor activity in nude BALB/c mice bearing early stage HCT116 human colon carcinoma xenografts[1]. Onalespib (40 or 60 mg/kg, i.p.) induces significant differences in EFS distribution compared to controls in 17% evaluable solid tumor xenografts, but in none of the ALL xenografts[2].

[Cell Assay]

In vitro testing is performed using DIMSCAN. Cells are incubated in the presence of Onalespib for 96 hours at concentrations from 1 nM to 10 μM[2].

[Animal admin]

HCT116 cells are injected SC into the right hind flank of male nude BALB/c mice. Tumours are apparent 7 to 10 days later. Mice are arranged into matched groups of 12 according to tumour volume giving a group mean of approximately 100 mm[3] at initiation of dosing. Tumour volumes are measured every 2 days. Statistical significance between groups is assessed using nonparametric one-way ANOVA. Mice are given the lactate salt of Onalespib using a repeated cycle of dosing of once per day for three days, no dose for three days, once per day for three days etc., for four dosing cycles at 60 mg/kg/dose (as free base equivalents) dissolved in 17.5% hydroxypropyl-β-cyclodextrin via the IP route. Control mice receive dose vehicle only via the same route. Tolerability is assessed by recording body weight, clinical observations and survival[1].

[References]

[1]. Woodhead AJ, et al. Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design. J Med Chem. 2010 Aug 26;53(16):5956-69.

[2]. Kang MH, et al. Initial testing (Stage 1) of AT13387, an HSP90 inhibitor, by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012 Jul 15;59(1):185-8.

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.2±0.1 g/cm3

[ Boiling Point ]:
605.7±55.0 °C at 760 mmHg

[ Molecular Formula ]:
C₂₄H₃₁N₃O₃

[ Molecular Weight ]:
409.521

[ Flash Point ]:
320.1±31.5 °C

[ Exact Mass ]:
409.236542

[ PSA ]:
67.25000

[ LogP ]:
1.52

[ Vapour Pressure ]:
0.0±1.8 mmHg at 25°C

[ Index of Refraction ]:
1.633

[ Storage condition ]:
-20℃

Safety Information

[ Hazard Codes ]:
Xi

[ HS Code ]:
2933990090

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

Customs

[ HS Code ]: 2933990090

[ Summary ]:
2933990090. heterocyclic compounds with nitrogen hetero-atom(s) only. VAT:17.0%. Tax rebate rate:13.0%. . MFN tariff:6.5%. General tariff:20.0%

Related Compounds

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