UNC0379 | CAS#1620401-82-2 | SETD8 Inhibitor

MedKoo Cat#: 406564 | Name: UNC0379

Description:

WARNING: This product is for research use only, not for human or veterinary use.

UNC0379 is a selective, substrate-competitive inhibitor of the lysine methyltransferase SETD8. UNC0379 is active in multiple biochemical assays. Its affinity to SETD8 was confirmed by ITC (isothermal titration calorimetry) and SPR (surface plasmon resonance) studies. Importantly, UNC0379 is selective for SETD8 over 15 other methyltransferases. The lysine methyltransferase SETD8 is the only known methyltransferase that catalyzes monomethylation of histone H4 lysine 20 (H4K20). Monomethylation of H4K20 has been implicated in regulating diverse biological processes including the DNA damage response.

Chemical Structure

UNC0379

CAS#1620401-82-2 (free base)

Theoretical Analysis

MedKoo Cat#: 406564

Name: UNC0379

CAS#: 1620401-82-2 (free base)

Chemical Formula: C23H35N5O2

Exact Mass: 413.2791

Molecular Weight: 413.56

Elemental Analysis: C, 66.80; H, 8.53; N, 16.93; O, 7.74

Price and Availability

Size	Price	Availability
10mg	USD 110.00	Ready to ship
25mg	USD 220.00	Ready to ship
50mg	USD 385.00	Ready to ship
100mg	USD 650.00	Ready to ship
200mg	USD 950.00	Ready to ship
500mg	USD 1,650.00	Ready to ship
1g	USD 2,650.00	Ready to ship
2g	USD 3,950.00	Ready to ship

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Related CAS #

1620401-83-3 (trifluoroacetate) 1620401-82-2 (free base)

Synonym

UNC0379, UNC-0379, UNC 0379

IUPAC/Chemical Name

6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine

InChi Key

WEXCGGWTIDNVNT-UHFFFAOYSA-N

InChi Code

InChI=1S/C23H35N5O2/c1-29-20-16-18-19(17-21(20)30-2)25-23(28-14-8-9-15-28)26-22(18)24-10-4-3-5-11-27-12-6-7-13-27/h16-17H,3-15H2,1-2H3,(H,24,25,26)

SMILES Code

COC1=C(OC)C=C(N=C(N2CCCC2)N=C3NCCCCCN4CCCC4)C3=C1

Appearance

Off-white to light beige 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).

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

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#SSC50102

QC Data

View QC data: current batch, Lot#SSC50102

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

UNC0379 is a selective, substrate-competitive inhibitor of lysine methyltransferase SETD8 (KMT5A) with an IC50 of 7.3 μM.

In vitro activity:

Application of UNC0379 to the IPF-MyoF resulted in a spindle-shaped morphology accompanied by a decrease in the expression of both α-SMA and ED-A-FN. These findings were supported by the results of the flowcytometric analysis (Supplementary Figure S3). α-SMA+ED-A-FN+ IPF-MyoF had high SSC that could be proportional to intracellular organelle complexity, which was significantly reduced by the treatment of IPF-MyoF with UNC0379. In conjunction with this phenomenon, the SSClowFSClow cell population mostly comprised of α-SMA–ED-A-FN– and α-SMAlowED-A-FN– fractions were negligible in the IPF-MyoF but significantly increased in response to the treatment with UNC0379. Along with the WB analysis, these results suggest that UNC0379 can induce the dedifferentiation of IPF-MyoF based on specific marker expression and morphology. Reference: Front Mol Biosci. 2020; 7: 192. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419601/

In vivo activity:

This study evaluated effects of SETD8 inhibition on in vivo tumor growth. Bioavailability and animal toxicology precluded treatment of mice with the SETD8 inhibitor UNC0379 (Ma et al., 2014a). The study therefore performed an ex-vivo tumorigenicity assay by exposing NB (neuroblastoma) cells to 2 μM UNC0379 or control solvent for 24 hr in vitro, then subcutaneously implanting treated NB cells into nude mice and monitoring tumor growth. Pharmacological inhibition of SETD8 showed decreased NB tumor growth in vivo and significantly reduced SY5Y (p ≤ 0.01) and NGP (p = 0.026) tumor growth (Figure 7A). Assessment of tumor lysates indicated that UNC0379 treatment reduced levels of p53K382me1 modification in xenografts (Figure 7A, insets). Kaplan-Meier survival curves revealed a statistically significant survival advantage for mice bearing ex-vivo UNC0379-treated NGP or SY5Y NB cells compared with control-treated NB cells (Figure 7B). These results suggest that a small molecule inhibitor of SETD8 may have therapeutic relevance. Reference: Cancer Cell. 2017 Jan 9; 31(1): 50–63. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233415/

	Solvent	mg/mL	mM
Solubility
	DMSO	50.7	122.52
	DMSO:PBS (pH 7.2) (1:1)	0.5	1.21
	DMF	20.0	48.36
	Ethanol	10.0	24.18

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 413.56 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.

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. Ugai K, Matsuda S, Mikami H, Shimada A, Misawa T, Nakamura H, Tatsumi K, Hatano M, Murayama T, Kasuya Y. Inhibition of the SET8 Pathway Ameliorates Lung Fibrosis Even Through Fibroblast Dedifferentiation. Front Mol Biosci. 2020 Aug 5;7:192. doi: 10.3389/fmolb.2020.00192. PMID: 32850975; PMCID: PMC7419601. 2. Ma A, Yu W, Li F, Bleich RM, Herold JM, Butler KV, Norris JL, Korboukh V, Tripathy A, Janzen WP, Arrowsmith CH, Frye SV, Vedadi M, Brown PJ, Jin J. Discovery of a selective, substrate-competitive inhibitor of the lysine methyltransferase SETD8. J Med Chem. 2014 Aug 14;57(15):6822-33. doi: 10.1021/jm500871s. Epub 2014 Jul 25. PMID: 25032507; PMCID: PMC4136711. 3. Wu J, Qiao K, Du Y, Zhang X, Cheng H, Peng L, Guo Z. Downregulation of histone methyltransferase SET8 inhibits progression of hepatocellular carcinoma. Sci Rep. 2020 Mar 11;10(1):4490. doi: 10.1038/s41598-020-61402-7. PMID: 32161353; PMCID: PMC7066161. 4. Veschi V, Liu Z, Voss TC, Ozbun L, Gryder B, Yan C, Hu Y, Ma A, Jin J, Mazur SJ, Lam N, Souza BK, Giannini G, Hager GL, Arrowsmith CH, Khan J, Appella E, Thiele CJ. Epigenetic siRNA and Chemical Screens Identify SETD8 Inhibition as a Therapeutic Strategy for p53 Activation in High-Risk Neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63. doi: 10.1016/j.ccell.2016.12.002. PMID: 28073004; PMCID: PMC5233415.

In vitro protocol:

In vivo protocol:

1. Wu J, Qiao K, Du Y, Zhang X, Cheng H, Peng L, Guo Z. Downregulation of histone methyltransferase SET8 inhibits progression of hepatocellular carcinoma. Sci Rep. 2020 Mar 11;10(1):4490. doi: 10.1038/s41598-020-61402-7. PMID: 32161353; PMCID: PMC7066161. 2. Veschi V, Liu Z, Voss TC, Ozbun L, Gryder B, Yan C, Hu Y, Ma A, Jin J, Mazur SJ, Lam N, Souza BK, Giannini G, Hager GL, Arrowsmith CH, Khan J, Appella E, Thiele CJ. Epigenetic siRNA and Chemical Screens Identify SETD8 Inhibition as a Therapeutic Strategy for p53 Activation in High-Risk Neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63. doi: 10.1016/j.ccell.2016.12.002. PMID: 28073004; PMCID: PMC5233415.

1: Yang X, Guan Y, Bayliss G, Zhao TC, Zhuang S. SET8 inhibition preserves PTEN to attenuate kidney cell apoptosis in cisplatin nephrotoxicity. Res Sq [Preprint]. 2024 Aug 14:rs.3.rs-4603170. doi: 10.21203/rs.3.rs-4603170/v1. PMID: 39184108; PMCID: PMC11343278. 2: Chen H, Hu J, Xiong X, Chen H, Liao Q, Lin B, Chen Y, Peng Y, Li Y, Cheng D, Li Z. SETD8 inhibits apoptosis and ferroptosis of Ewing's sarcoma through YBX1/RAC3 axis. Cell Death Dis. 2024 Jul 10;15(7):494. doi: 10.1038/s41419-024-06882-5. PMID: 38987564; PMCID: PMC11237091. 3: Peng X, Ma L, Chen X, Tang F, Zong X. Inhibition of FBP1 expression by KMT5A through TWIST1 methylation is one of the mechanisms leading to chemoresistance in breast cancer. Oncol Rep. 2024 Aug;52(2):110. doi: 10.3892/or.2024.8769. Epub 2024 Jul 4. PMID: 38963044; PMCID: PMC11258601. 4: Della Monica R, Buonaiuto M, Cuomo M, Pagano C, Trio F, Costabile D, de Riso G, Cicala FS, Raia M, Franca RA, Del Basso De Caro M, Sorrentino D, Navarra G, Coppola L, Tripodi L, Pastore L, Hench J, Frank S, Schonauer C, Catapano G, Bifulco M, Chiariotti L, Visconti R. Targeted inhibition of the methyltransferase SETD8 synergizes with the Wee1 inhibitor adavosertib in restraining glioblastoma growth. Cell Death Dis. 2023 Sep 27;14(9):638. doi: 10.1038/s41419-023-06167-3. PMID: 37758718; PMCID: PMC10533811. 5: Wang X, Cao C, Tan X, Liao X, Du X, Wang X, Liu T, Gong D, Hu Z, Tian X. SETD8, a frequently mutated gene in cervical cancer, enhances cisplatin sensitivity by impairing DNA repair. Cell Biosci. 2023 Jun 12;13(1):107. doi: 10.1186/s13578-023-01054-y. PMID: 37308924; PMCID: PMC10262521. 6: Chen L, Yang C, Tang SB, Long QY, Chen JD, Wu M, Li LY. Inhibition of histone methyltransferase SETD8 represses DNA virus replication. Cell Insight. 2022 May 25;1(3):100033. doi: 10.1016/j.cellin.2022.100033. Erratum in: Cell Insight. 2024 Jan 30;3(1):100148. doi: 10.1016/j.cellin.2024.100148. PMID: 37193046; PMCID: PMC10120311. 7: Li X, Liu Z, Xia C, Yan K, Fang Z, Fan Y. SETD8 stabilized by USP17 epigenetically activates SREBP1 pathway to drive lipogenesis and oncogenesis of ccRCC. Cancer Lett. 2022 Feb 28;527:150-163. doi: 10.1016/j.canlet.2021.12.018. Epub 2021 Dec 21. PMID: 34942305. 8: Liu M, Shi Y, Hu Q, Qin Y, Ji S, Liu W, Zhuo Q, Fan G, Ye Z, Song C, Yu X, Xu X, Xu W. SETD8 induces stemness and epithelial-mesenchymal transition of pancreatic cancer cells by regulating ROR1 expression. Acta Biochim Biophys Sin (Shanghai). 2021 Dec 8;53(12):1614-1624. doi: 10.1093/abbs/gmab140. PMID: 34599596. 9: Herviou L, Ovejero S, Izard F, Karmous-Gadacha O, Gourzones C, Bellanger C, De Smedt E, Ma A, Vincent L, Cartron G, Jin J, De Bruyne E, Grimaud C, Julien E, Moreaux J. Targeting the methyltransferase SETD8 impairs tumor cell survival and overcomes drug resistance independently of p53 status in multiple myeloma. Clin Epigenetics. 2021 Sep 16;13(1):174. doi: 10.1186/s13148-021-01160-z. PMID: 34530900; PMCID: PMC8447659. 10: Chen P, Zhu H, Mao Y, Zhuo M, Yu Y, Chen M, Zhao Q, Li L, Wu M, Ye M. SETD8 involved in the progression of inflammatory bowel disease via epigenetically regulating p62 expression. J Gastroenterol Hepatol. 2021 Oct;36(10):2850-2863. doi: 10.1111/jgh.15550. Epub 2021 May 29. PMID: 33991018. 11: Wada M, Kukita A, Sone K, Hamamoto R, Kaneko S, Komatsu M, Takahashi Y, Inoue F, Kojima M, Honjoh H, Taguchi A, Kashiyama T, Miyamoto Y, Tanikawa M, Tsuruga T, Mori-Uchino M, Wada-Hiraike O, Osuga Y, Fujii T. Epigenetic Modifier SETD8 as a Therapeutic Target for High-Grade Serous Ovarian Cancer. Biomolecules. 2020 Dec 16;10(12):1686. doi: 10.3390/biom10121686. PMID: 33339442; PMCID: PMC7766894. 12: Ugai K, Matsuda S, Mikami H, Shimada A, Misawa T, Nakamura H, Tatsumi K, Hatano M, Murayama T, Kasuya Y. Inhibition of the SET8 Pathway Ameliorates Lung Fibrosis Even Through Fibroblast Dedifferentiation. Front Mol Biosci. 2020 Aug 5;7:192. doi: 10.3389/fmolb.2020.00192. PMID: 32850975; PMCID: PMC7419601. 13: Wu J, Qiao K, Du Y, Zhang X, Cheng H, Peng L, Guo Z. Downregulation of histone methyltransferase SET8 inhibits progression of hepatocellular carcinoma. Sci Rep. 2020 Mar 11;10(1):4490. doi: 10.1038/s41598-020-61402-7. PMID: 32161353; PMCID: PMC7066161. 14: Gursoy-Yuzugullu O, Carman C, Serafim RB, Myronakis M, Valente V, Price BD. Epigenetic therapy with inhibitors of histone methylation suppresses DNA damage signaling and increases glioma cell radiosensitivity. Oncotarget. 2017 Apr 11;8(15):24518-24532. doi: 10.18632/oncotarget.15543. PMID: 28445939; PMCID: PMC5421867. 15: Veschi V, Liu Z, Voss TC, Ozbun L, Gryder B, Yan C, Hu Y, Ma A, Jin J, Mazur SJ, Lam N, Souza BK, Giannini G, Hager GL, Arrowsmith CH, Khan J, Appella E, Thiele CJ. Epigenetic siRNA and Chemical Screens Identify SETD8 Inhibition as a Therapeutic Strategy for p53 Activation in High-Risk Neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63. doi: 10.1016/j.ccell.2016.12.002. PMID: 28073004; PMCID: PMC5233415. 16: Ma A, Yu W, Xiong Y, Butler KV, Brown PJ, Jin J. Structure-activity relationship studies of SETD8 inhibitors. Medchemcomm. 2014 Dec;5(12):1892-1898. doi: 10.1039/C4MD00317A. PMID: 25554733; PMCID: PMC4278651. 17: Ma A, Yu W, Li F, Bleich RM, Herold JM, Butler KV, Norris JL, Korboukh V, Tripathy A, Janzen WP, Arrowsmith CH, Frye SV, Vedadi M, Brown PJ, Jin J. Discovery of a selective, substrate-competitive inhibitor of the lysine methyltransferase SETD8. J Med Chem. 2014 Aug 14;57(15):6822-33. doi: 10.1021/jm500871s. Epub 2014 Jul 25. PMID: 25032507; PMCID: PMC4136711.