CAS No. : 1316214-52-4

Product Details
For research use only. Not Intended for Therapeutic Use!
Cat No:I001219
Synonyms:ACY-1215; ACY1215; ACY 1215; N-[7-(hydroxyamino)-7-oxoheptyl]-2-(N-phenylanilino)pyrimidine-5-carboxamide
Molecular Formula:C₂₄H₂₇N₅O₃
Molecular Weight:433.5
IC50:5 nM
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Appearance:white to off-white solid powder
Purity: > 98%
Cat No:I001219
Cas No:1316214-52-4

Rocilinostat (cas 1316214-52-4), also known as ACY-1215, is a selective HDAC6 inhibitor with IC50 of 5 nM; >10-fold more selective for HDAC6 than HDAC1/2/3 (class I HDACs) with slight activity against HDAC8, minimal activity against HDAC4/5/7/9/11, Sirtuin1, and Sirtuin2. ACY-1215 selectively targets and binds to HDAC6, thereby disrupting the Hsp90 protein chaperone system through hyperacetylation of Hsp90 and preventing the subsequent aggresomal protein degradation. This leads to an accumulation of unfolded and misfolded ubiquitinated proteins and may eventually induce cancer cell apoptosis, and inhibition of cancer cell growth. HDAC6, a class II HDAC deacetylase located in the cytoplasm, appears to play a key role in the formation and activation of the aggresomes needed for degradation of misfolded proteins. Compared to non-selective HDAC inhibitor, ACY-1215 is able to reduce the toxic effects on normal, healthy cells.

Originator: Dana-Farber Cancer Institute; Harvard University
Developer: Columbia University; Dana-Farber Cancer Institute; Massachusetts General Hospital; Regenacy Pharmaceuticals; University of Texas M. D. Anderson Cancer Center
Class: Amides; Antineoplastics; Hydroxamic acids; Pyrimidines; Small molecules
Mechanism of Action: HDAC6 protein inhibitors
Orphan Drug Status: No
New Molecular Entity: Yes
1. Oncol Rep. 2017 Feb;37(2):1270-1276. doi: 10.3892/or.2016.5340. Epub 2016 Dec 28.
ACY-1215 accelerates vemurafenib induced cell death of BRAF-mutant melanoma cells via induction of ER stress and inhibition of ERK activation.
Peng U(1), Wang Z(2), Pei S(1), Ou Y(1), Hu P(2), Liu W(2), Song J(1).
Author information:
(1)Department of Dermatology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China. (2)School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, P.R. China.
BRAFV600E mutation is found in ~50% of melanoma patients and BRAFV600E kinase activity inhibitor, vemurafenib, has achieved a remarkable clinical response rate. However, most patients treated with vemurafenib eventually develop resistance. Overcoming primary and secondary resistance to selective BRAF inhibitors remains one of the most critically compelling challenges for these patients. HDAC6 has been shown to confer resistance to chemotherapy in several types of cancer. Few studies focused on the role of HDAC6 in vemurafenib resistance. Here we showed that overexpression of HDAC6 confers resistance to vemurafenib in BRAF-mutant A375 cells. ACY-1215, a selective HDAC6 inhibitor, inhibits the proliferation and induces the apoptosis of A375 cells. Moreover, ACY-1215 sensitizes A375 cells to vemurafenib induced cell proliferation inhibition and apoptosis induction, which occur partly through induction of endoplasmic reticulum (ER) stress and inactivation of extracellular signal-regulated kinase (ERK). Taken together, our results suggest that the inhibition of HDAC6 may be a promising strategy for the treatment of melanoma and overcoming resistance to vemurafenib.
2. Br J Haematol. 2015 May;169(3):423-34. doi: 10.1111/bjh.13315. Epub 2015 Feb 23.
Ricolinostat (ACY-1215) induced inhibition of aggresome formation accelerates carfilzomib-induced multiple myeloma cell death.
Mishima Y(1), Santo L, Eda H, Cirstea D, Nemani N, Yee AJ, O/'Donnell E, Selig MK, Quayle SN, Arastu-Kapur S, Kirk C, Boise LH, Jones SS, Raje N.
Author information:
(1)Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
Proteasome inhibition induces the accumulation of aggregated misfolded/ubiquitinated proteins in the aggresome; conversely, histone deacetylase 6 (HDAC6) inhibition blocks aggresome formation. Although this rationale has been the basis of proteasome inhibitor (PI) and HDAC6 inhibitor combination studies, the role of disruption of aggresome formation by HDAC6 inhibition has not yet been studied in multiple myeloma (MM). The present study aimed to evaluate the impact of carfilzomib (CFZ) in combination with a selective HDAC6 inhibitor (ricolinostat) in MM cells with respect to the aggresome-proteolysis pathway. We observed that combination treatment of CFZ with ricolinostat triggered synergistic anti-MM effects, even in bortezomib-resistant cells. Immunofluorescent staining showed that CFZ increased the accumulation of ubiquitinated proteins and protein aggregates in the cytoplasm, as well as the engulfment of aggregated ubiquitinated proteins by autophagosomes, which was blocked by ricolinostat. Electron microscopy imaging showed increased autophagy triggered by CFZ, which was inhibited by the addition of ACY-1215. Finally, an in vivo mouse xenograft study confirmed a decrease in tumour volume, associated with apoptosis, following treatment with CFZ in combination with ricolinostat. Our results suggest that ricolinostat inhibits aggresome formation, caused by CFZ-induced inhibition of the proteasome pathway, resulting in enhanced apoptosis in MM cells.
3. Blood. 2012 Mar 15;119(11):2579-89. doi: 10.1182/blood-2011-10-387365. Epub 2012 Jan 19.
Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma.
Santo L(1), Hideshima T, Kung AL, Tseng JC, Tamang D, Yang M, Jarpe M, van Duzer JH, Mazitschek R, Ogier WC, Cirstea D, Rodig S, Eda H, Scullen T, Canavese M, Bradner J, Anderson KC, Jones SS, Raje N.
Author information:
(1)Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
Histone deacetylase (HDAC) enzymatic activity has been linked to the transcription of DNA in cancers including multiple myeloma (MM). Therefore, HDAC inhibitors used alone and in combination are being actively studied as novel therapies in MM. In the present study, we investigated the preclinical activity of ACY-1215, an HDAC6-selective inhibitor, alone and in combination with bortezomib in MM. Low doses of ACY-1215 combined with bortezomib triggered synergistic anti-MM activity, resulting in protracted endoplasmic reticulum stress and apoptosis via activation of caspase-3, caspase-8, and caspase-9 and poly (ADP) ribosome polymerase. In vivo, the anti-MM activity of ACY-1215 in combination with bortezomib was confirmed using 2 different xenograft SCID mouse models: human MM injected subcutaneously (the plasmacytoma model) and luciferase-expressing human MM injected intravenously (the disseminated MM model). Tumor growth was significantly delayed and overall survival was significantly prolonged in animals treated with the combination therapy. Pharmacokinetic data showed peak plasma levels of ACY-1215 at 4 hours after treatment coincident with an increase in acetylated α-tubulin, a marker of HDAC6 inhibition, by immunohistochemistry and Western blot analysis. These studies provide preclinical rationale for acetylated α-tubulin use as a pharmacodynamic biomarker in future clinical trials.
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