ACY-1215 Chemical Properties

Melting point:

189 - 191°C

Density 

1.239±0.06 g/cm3(Predicted)

storage temp. 

-20°C Freezer

solubility 

DMSO (Slightly), Methanol (Slightly)

pka

9.47±0.20(Predicted)

form 

Solid

color 

White to Off-White

ACY-1215 Usage And Synthesis

Description

ACY-1215 is an inhibitor of histone deacetylase 6 (HDAC6; IC₅₀ = 5 nM). It is at least 10-fold less active against other HDACs in enzymatic assays. ACY-1215 shows synergistic activity with the proteasome inhibitor bortezomib against multiple myeloma (MM) cells, inducing protracted endoplasmic reticulum stress and apoptosis. ACY-1215 combined with proteasome inhibitors suppresses tumor growth and increases survival in mice with MM and mantle cell lymphoma xenografts. A multicenter phase I trial examining ACY-1215 combined with the E3 ligase inhibitor lenalidomide and dexamethasone in multiple myeloma found inhibition of HDAC6 in vivo. ACY-1215 also diminishes liver cyst development and fibrosis in a rat model of polycystic liver disease.

Uses

This compound acts as a selective HDAC-6 (histone deacetylase) inihibitor. HDAC is linked to the transcription of DNA in cancers, including multiple myeloma (MM).

Definition

ChEBI: N-[7-(hydroxyamino)-7-oxoheptyl]-2-(N-phenylanilino)-5-pyrimidinecarboxamide is a pyrimidinecarboxylic acid.

Synthesis

Compound 6 (CAS:1316216-07-5) (2.0 g, 4.6 mmol) was taken as raw material and stirred with sodium hydroxide (2N, 20 mL) in a solvent mixture of methanol (50 mL) and dichloromethane (25 mL) for 10 minutes at 0°C. Subsequently, hydroxylamine (50%, 10 mL) pre-cooled to 0°C was added to the above mixture. The reaction mixture was continued to be stirred at room temperature for 20 minutes. Upon completion of the reaction, the solvent was removed by distillation under reduced pressure and the resulting mixture was neutralized with 1 M hydrochloric acid to produce a white precipitate. The crude product was filtered and purified by preparative high performance liquid chromatography (pre-HPLC) to give the final target product 2-(diphenylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]pyrimidine-5-carboxamide as a white solid (950 mg, 48% yield).

in vivo

target

HDAC6

IC 50

HDAC6: 4.7 nM (IC₅₀); HDAC2: 48 nM (IC₅₀); HDAC3: 51 nM (IC₅₀); HDAC1: 58 nM (IC₅₀); HDAC8: 100 nM (IC₅₀); HDAC7: 1400 nM (IC₅₀); HDAC5: 5000 nM (IC₅₀); HDAC4: 7000 nM (IC₅₀)

References

[1] Patent: WO2011/91213, 2011, A2. Location in patent: Page/Page column 73; 75-76
[2] Patent: WO2013/13113, 2013, A2. Location in patent: Page/Page column 70
[3] Patent: US2015/99744, 2015, A1. Location in patent: Paragraph 0237
[4] Patent: US2015/105384, 2015, A1. Location in patent: Paragraph 0406
[5] Patent: US2015/105358, 2015, A1. Location in patent: Paragraph 0396-0397

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