Rocilinostat
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MedKoo CAT#: 205808

CAS#: 1316214-52-4

Description: 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.

Chemical Structure

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Rocilinostat
CAS# 1316214-52-4
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 205808
Name: Rocilinostat
CAS#: 1316214-52-4
Chemical Formula: C24H27N5O3
Exact Mass: 433.21
Molecular Weight: 433.503
Elemental Analysis: C, 66.50; H, 6.28; N, 16.16; O, 11.07

Price and Availability

Size Price Availability Quantity
25mg USD 90 Ready to ship
50mg USD 150 Ready to ship
100mg USD 225 Ready to ship
200mg USD 400 Ready to ship
500mg USD 700 Ready to ship
1g USD 1250 Ready to ship
Bulk inquiry

Synonym: ACY-1215; ACY1215; ACY 1215; Rocilinostat; Ricolinostat; ACY-1215

IUPAC/Chemical Name: 2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide

InChi Key: QGZYDVAGYRLSKP-UHFFFAOYSA-N

InChi Code: InChI=1S/C24H27N5O3/c30-22(28-32)15-9-1-2-10-16-25-23(31)19-17-26-24(27-18-19)29(20-11-5-3-6-12-20)21-13-7-4-8-14-21/h3-8,11-14,17-18,32H,1-2,9-10,15-16H2,(H,25,31)(H,28,30)

SMILES Code: O=C(C1=CN=C(N(C2=CC=CC=C2)C3=CC=CC=C3)N=C1)NCCCCCCC(NO)=O

Appearance: Pale peach fluffy 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).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info: ACY-1215 selectively inhibits the intracellular enzyme HDAC6, leading to inactivation of the “aggresome” pathway for degradation of damaged proteins. The resultant accumulation of excess waste protein in malignant cells triggers programmed cell death, called “apoptosis,” with little or no effect on normal cells. Currently available HDAC drugs non-selectively target multiple HDAC enzymes including those of Class I, resulting in dysregulated expression of numerous genes in normal cells as well as cancer cells. Side effects commonly associated with non-selective HDAC drugs include gastrointestinal dysfunction, lowered blood platelet levels and risk of hemorrhage, and profound fatigue as well as potential for severe cardiac complications. Selective inhibition of HDAC6 is expected to reduce or eliminate these often-severe side effects associated with non-selective HDAC inhibition, and may enable the development of optimized treatment regimens including maximally effective combination drug therapies. (source: http://www.acetylon.com/).       ACY-1215 demonstrated potent and selective inhibitory activity against HDAC6, with an enzymatic IC50 value of 5nM. ACY-1215 is 12-, 10-, and 11-fold less active against HDAC1, HDAC2, and HDAC3 (class I HDACs), respectively. ACY-1215 has minimal activity  (IC50 1 M) against HDAC4, HDAC5, HDAC7, HDAC9, HDAC11, Sirtuin1, and Sirtuin2, and has slight activity against HDAC8 (IC50 0.1 M).  ACY-1215 demonstrated potent and selective inhibitory activity against HDAC6, with an enzymatic IC50 value of 5nM. ACY-1215 is 12-, 10-, and 11-fold less active against HDAC1, HDAC2, and HDAC3 (class I HDACs), respectively. ACY-1215 has minimal activity  (IC50 1 M) against HDAC4, HDAC5, HDAC7, HDAC9, HDAC11, Sirtuin1, and Sirtuin2, and has slight activity against HDAC8 (IC50 0.1 M).    

Biological target: Ricolinostat (ACY-1215) is a selective HDAC6 inhibitor with an IC50 of 5 nM.
In vitro activity: The HDAC6-selective inhibitor ACY-1215 inhibited cellular proliferation and caused G2/M arrest and apoptosis via PI3K/AKT/mTOR and ERK pathways. Regulatory proteins involved in G2/M transition and dysregulated in ESCC were variously downregulated (survivin, cdc2, P-P53, and cyclin A2) and upregulated (P21) by ACY-1215 treatment. Survivin is also an inhibitor of apoptosis, wherein survivin inhibition amplifies caspase activation. In addition to increasing apoptosis through the commonly activated caspase pathway, ACY-1215 also increased Bax and Bim protein expression and reduced Bcl2 protein levels. ACY-1215 not only effectively inhibited phosphorylation ERK, but also inhibited PI3K/AKT/mTOR signaling pathways. Reference: Cell Death Dis. 2018 Jul 26;9(8):817. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062526/
In vivo activity: To further validate the effects of ACY-1215 in vivo, EC109 cells were injected subcutaneously into the BALB/c nude mice. Ten days after injection, mice were divided into control group and ACY-1215 treatment group, and the latter group was treated with ACY-1215 50 mg/kg via intraperitoneally. Following three cycles of therapy, the ACY-1215 treatment group led to a statistically significant tumor growth slower than those in the control group (Fig. 8a–c). These findings suggested that ACY-1215 inhibited tumor growth in vivo. Reference: Cell Death Dis. 2018 Jul 26;9(8):817. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062526/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 71.0 163.78
DMF 5.0 11.53
DMSO:PBS (pH 7.2) (1:1) 0.5 1.15

Preparing Stock Solutions

The following data is based on the product molecular weight 433.50 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Cao J, Lv W, Wang L, Xu J, Yuan P, Huang S, He Z, Hu J. Ricolinostat (ACY-1215) suppresses proliferation and promotes apoptosis in esophageal squamous cell carcinoma via miR-30d/PI3K/AKT/mTOR and ERK pathways. Cell Death Dis. 2018 Jul 26;9(8):817. doi: 10.1038/s41419-018-0788-2. PMID: 30050135; PMCID: PMC6062526. 2. Li L, Liu F, Huang W, Wang J, Wan Y, Li M, Pang Y, Yin Z. Ricolinostat (ACY-1215) inhibits VEGF expression via PI3K/AKT pathway and promotes apoptosis in osteoarthritic osteoblasts. Biomed Pharmacother. 2019 Oct;118:109357. doi: 10.1016/j.biopha.2019.109357. Epub 2019 Aug 21. PMID: 31548177.
In vitro protocol: 1. Cao J, Lv W, Wang L, Xu J, Yuan P, Huang S, He Z, Hu J. Ricolinostat (ACY-1215) suppresses proliferation and promotes apoptosis in esophageal squamous cell carcinoma via miR-30d/PI3K/AKT/mTOR and ERK pathways. Cell Death Dis. 2018 Jul 26;9(8):817. doi: 10.1038/s41419-018-0788-2. PMID: 30050135; PMCID: PMC6062526.
In vivo protocol: 1. Li L, Liu F, Huang W, Wang J, Wan Y, Li M, Pang Y, Yin Z. Ricolinostat (ACY-1215) inhibits VEGF expression via PI3K/AKT pathway and promotes apoptosis in osteoarthritic osteoblasts. Biomed Pharmacother. 2019 Oct;118:109357. doi: 10.1016/j.biopha.2019.109357. Epub 2019 Aug 21. PMID: 31548177.

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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.