ACY-1215 (Rocilinostat)
Rocilinostat, previously known as ACY-1215, is an orally bioavailable, specific inhibitor of histone deacetylase 6 (HDAC6) with potential antineoplastic activity. 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.
1: Amengual JE, Johannet P, Lombardo M, Zullo K, Hoehn D, Bhagat G, Scotto L, Jirau-Serrano X, Radeski D, Heinen J, Jiang H, Cremers S, Zhang Y, Jones S, O'Connor OA. Dual Targeting of Protein Degradation Pathways with the Selective HDAC6 Inhibitor ACY-1215 and Bortezomib Is Synergistic in Lymphoma. Clin Cancer Res. 2015 Oct 15;21(20):4663-75. doi: 10.1158/1078-0432.CCR-14-3068. PubMed PMID: 26116270; PubMed Central PMCID: PMC4609274.
2: Mishima Y, 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. Ricolinostat (ACY-1215) induced inhibition of aggresome formation accelerates carfilzomib-induced multiple myeloma cell death. Br J Haematol. 2015 May;169(3):423-34. doi: 10.1111/bjh.13315. PubMed PMID: 25709080.
3: Santo L, 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. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood. 2012 Mar 15;119(11):2579-89. doi: 10.1182/blood-2011-10-387365. PubMed PMID: 22262760; PubMed Central PMCID: PMC3337713.
4: Zhang L, Liu C, Wu J, Tao JJ, Sui XL, Yao ZG, Xu YF, Huang L, Zhu H, Sheng SL, Qin C. Tubastatin A/ACY-1215 improves cognition in Alzheimer's disease transgenic mice. J Alzheimers Dis. 2014;41(4):1193-205. doi: 10.3233/JAD-140066. PubMed PMID: 24844691.
5: Peng U, Wang Z, Pei S, Ou Y, Hu P, Liu W, Song J. ACY-1215 accelerates vemurafenib induced cell death of BRAF-mutant melanoma cells via induction of ER stress and inhibition of ERK activation. Oncol Rep. 2017 Feb;37(2):1270-1276. doi: 10.3892/or.2016.5340. PubMed PMID: 28035401.
6: Tsuji G, Okiyama N, Villarroel VA, Katz SI. Histone deacetylase 6 inhibition impairs effector CD8 T-cell functions during skin inflammation. J Allergy Clin Immunol. 2015 May;135(5):1228-39. doi: 10.1016/j.jaci.2014.10.002. PubMed PMID: 25458911; PubMed Central PMCID: PMC4426217.
7: Gradilone SA, Habringer S, Masyuk TV, Howard BN, Masyuk AI, Larusso NF. HDAC6 is overexpressed in cystic cholangiocytes and its inhibition reduces cystogenesis. Am J Pathol. 2014 Mar;184(3):600-8. doi: 10.1016/j.ajpath.2013.11.027. PubMed PMID: 24434010; PubMed Central PMCID: PMC3936326.
8: Li S, Liu X, Chen X, Zhang L, Wang X. Histone deacetylase 6 promotes growth of glioblastoma through inhibition of SMAD2 signaling. Tumour Biol. 2015 Dec;36(12):9661-5. doi: 10.1007/s13277-015-3747-x. PubMed PMID: 26150340.
9: Amengual JE, Prabhu SA, Lombardo M, Zullo KM, Johannet PM, Gonzalez Y, Scotto L, Jirau-Serrano X, Wei Y, Duong JK, Nandakumar R, Cremers S, Verma A, Elemento O, O'Connor OA. Mechanisms of Acquired Drug Resistance to the HDAC6 Selective Inhibitor Ricolinostat Reveals Rational Drug : Drug Combination with Ibrutinib. Clin Cancer Res. 2016 Dec 19. pii: clincanres.2022.2016. [Epub ahead of print] PubMed PMID: 27993968.
10: Benoy V, Vanden Berghe P, Jarpe M, Van Damme P, Robberecht W, Van Den Bosch L. Development of Improved HDAC6 Inhibitors as Pharmacological Therapy for Axonal Charcot-Marie-Tooth Disease. Neurotherapeutics. 2016 Dec 12. [Epub ahead of print] PubMed PMID: 27957719.
11: Dasmahapatra G, Patel H, Friedberg J, Quayle SN, Jones SS, Grant S. In vitro and in vivo interactions between the HDAC6 inhibitor ricolinostat (ACY1215) and the irreversible proteasome inhibitor carfilzomib in non-Hodgkin lymphoma cells. Mol Cancer Ther. 2014 Dec;13(12):2886-97. doi: 10.1158/1535-7163.MCT-14-0220. PubMed PMID: 25239935; PubMed Central PMCID: PMC4304772.
12: Yang Z, Wang T, Wang F, Niu T, Liu Z, Chen X, Long C, Tang M, Cao D, Wang X, Xiang W, Yi Y, Ma L, You J, Chen L. Discovery of Selective Histone Deacetylase 6 Inhibitors Using the Quinazoline as the Cap for the Treatment of Cancer. J Med Chem. 2016 Feb 25;59(4):1455-70. doi: 10.1021/acs.jmedchem.5b01342. PubMed PMID: 26443078.
13: Mithraprabhu S, Khong T, Jones SS, Spencer A. Histone deacetylase (HDAC) inhibitors as single agents induce multiple myeloma cell death principally through the inhibition of class I HDAC. Br J Haematol. 2013 Aug;162(4):559-62. doi: 10.1111/bjh.12388. PubMed PMID: 23692150.
14: Huang P, Almeciga-Pinto I, Jarpe M, van Duzer JH, Mazitschek R, Yang M, Jones SS, Quayle SN. Selective HDAC inhibition by ACY-241 enhances the activity of paclitaxel in solid tumor models. Oncotarget. 2016 Dec 1. doi: 10.18632/oncotarget.13738. [Epub ahead of print] PubMed PMID: 27926524.
15: Yee AJ, Bensinger WI, Supko JG, Voorhees PM, Berdeja JG, Richardson PG, Libby EN, Wallace EE, Birrer NE, Burke JN, Tamang DL, Yang M, Jones SS, Wheeler CA, Markelewicz RJ, Raje NS. Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial. Lancet Oncol. 2016 Nov;17(11):1569-1578. doi: 10.1016/S1470-2045(16)30375-8. PubMed PMID: 27646843.
2: Mishima Y, 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. Ricolinostat (ACY-1215) induced inhibition of aggresome formation accelerates carfilzomib-induced multiple myeloma cell death. Br J Haematol. 2015 May;169(3):423-34. doi: 10.1111/bjh.13315. PubMed PMID: 25709080.
3: Santo L, 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. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood. 2012 Mar 15;119(11):2579-89. doi: 10.1182/blood-2011-10-387365. PubMed PMID: 22262760; PubMed Central PMCID: PMC3337713.
4: Zhang L, Liu C, Wu J, Tao JJ, Sui XL, Yao ZG, Xu YF, Huang L, Zhu H, Sheng SL, Qin C. Tubastatin A/ACY-1215 improves cognition in Alzheimer's disease transgenic mice. J Alzheimers Dis. 2014;41(4):1193-205. doi: 10.3233/JAD-140066. PubMed PMID: 24844691.
5: Peng U, Wang Z, Pei S, Ou Y, Hu P, Liu W, Song J. ACY-1215 accelerates vemurafenib induced cell death of BRAF-mutant melanoma cells via induction of ER stress and inhibition of ERK activation. Oncol Rep. 2017 Feb;37(2):1270-1276. doi: 10.3892/or.2016.5340. PubMed PMID: 28035401.
6: Tsuji G, Okiyama N, Villarroel VA, Katz SI. Histone deacetylase 6 inhibition impairs effector CD8 T-cell functions during skin inflammation. J Allergy Clin Immunol. 2015 May;135(5):1228-39. doi: 10.1016/j.jaci.2014.10.002. PubMed PMID: 25458911; PubMed Central PMCID: PMC4426217.
7: Gradilone SA, Habringer S, Masyuk TV, Howard BN, Masyuk AI, Larusso NF. HDAC6 is overexpressed in cystic cholangiocytes and its inhibition reduces cystogenesis. Am J Pathol. 2014 Mar;184(3):600-8. doi: 10.1016/j.ajpath.2013.11.027. PubMed PMID: 24434010; PubMed Central PMCID: PMC3936326.
8: Li S, Liu X, Chen X, Zhang L, Wang X. Histone deacetylase 6 promotes growth of glioblastoma through inhibition of SMAD2 signaling. Tumour Biol. 2015 Dec;36(12):9661-5. doi: 10.1007/s13277-015-3747-x. PubMed PMID: 26150340.
9: Amengual JE, Prabhu SA, Lombardo M, Zullo KM, Johannet PM, Gonzalez Y, Scotto L, Jirau-Serrano X, Wei Y, Duong JK, Nandakumar R, Cremers S, Verma A, Elemento O, O'Connor OA. Mechanisms of Acquired Drug Resistance to the HDAC6 Selective Inhibitor Ricolinostat Reveals Rational Drug : Drug Combination with Ibrutinib. Clin Cancer Res. 2016 Dec 19. pii: clincanres.2022.2016. [Epub ahead of print] PubMed PMID: 27993968.
10: Benoy V, Vanden Berghe P, Jarpe M, Van Damme P, Robberecht W, Van Den Bosch L. Development of Improved HDAC6 Inhibitors as Pharmacological Therapy for Axonal Charcot-Marie-Tooth Disease. Neurotherapeutics. 2016 Dec 12. [Epub ahead of print] PubMed PMID: 27957719.
11: Dasmahapatra G, Patel H, Friedberg J, Quayle SN, Jones SS, Grant S. In vitro and in vivo interactions between the HDAC6 inhibitor ricolinostat (ACY1215) and the irreversible proteasome inhibitor carfilzomib in non-Hodgkin lymphoma cells. Mol Cancer Ther. 2014 Dec;13(12):2886-97. doi: 10.1158/1535-7163.MCT-14-0220. PubMed PMID: 25239935; PubMed Central PMCID: PMC4304772.
12: Yang Z, Wang T, Wang F, Niu T, Liu Z, Chen X, Long C, Tang M, Cao D, Wang X, Xiang W, Yi Y, Ma L, You J, Chen L. Discovery of Selective Histone Deacetylase 6 Inhibitors Using the Quinazoline as the Cap for the Treatment of Cancer. J Med Chem. 2016 Feb 25;59(4):1455-70. doi: 10.1021/acs.jmedchem.5b01342. PubMed PMID: 26443078.
13: Mithraprabhu S, Khong T, Jones SS, Spencer A. Histone deacetylase (HDAC) inhibitors as single agents induce multiple myeloma cell death principally through the inhibition of class I HDAC. Br J Haematol. 2013 Aug;162(4):559-62. doi: 10.1111/bjh.12388. PubMed PMID: 23692150.
14: Huang P, Almeciga-Pinto I, Jarpe M, van Duzer JH, Mazitschek R, Yang M, Jones SS, Quayle SN. Selective HDAC inhibition by ACY-241 enhances the activity of paclitaxel in solid tumor models. Oncotarget. 2016 Dec 1. doi: 10.18632/oncotarget.13738. [Epub ahead of print] PubMed PMID: 27926524.
15: Yee AJ, Bensinger WI, Supko JG, Voorhees PM, Berdeja JG, Richardson PG, Libby EN, Wallace EE, Birrer NE, Burke JN, Tamang DL, Yang M, Jones SS, Wheeler CA, Markelewicz RJ, Raje NS. Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial. Lancet Oncol. 2016 Nov;17(11):1569-1578. doi: 10.1016/S1470-2045(16)30375-8. PubMed PMID: 27646843.
| Chemical | |
|---|---|
| CAS Num | 1316214-52-4 |
| Chemical Formula | C24H27N5O3 |
| Molecular Weight | 433.50288 |
| IUPAC Chemical Name | 2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide |
| Exact Mass | 433.21139 |
| Elemental Analysis | C, 66.50; H, 6.28; N, 16.16; O, 11.07 |
| Synonym | ACY-1215; ACY1215; ACY 1215; Rocilinostat |
| Solubility | Soluble in DMSO, not in water |
| SMILES Code | O=C(C1=CN=C(N(C2=CC=CC=C2)C3=CC=CC=C3)N=C1)NCCCCCCC(NO)=O |
| Biological | |
| Targets and Effects | histone deacetylase 6 (HDAC6) inhibitor |
| Pathways | Apoptosis |
| Physical | |
| Appearance | white to off-white solid powder |
| Purity | >98% (or refer to the Certificate of Analysis) |
| Shipping Condition | Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs. |
| Storage Condition | Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years). |
| Shelf Life | >2 years if stored properly |
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