UNC0642 | CAS#1481677-78-4 | G9a/GLP Inhibitor

MedKoo Cat#: 407288 | Name: UNC0642

Description:

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

UNC0642 is a potent, selective inhibitor of G9a/GLP with improved PK properties. UNC0642 exhibits an in vitro IC50 <15 nM with selectivity > 100-fold over 13 other HMTs and selected representatives of kinases, ion channels, 7TMs, and other epigenetic proteins. In cells, UNC0642 results in a potent reduction of H3K9me2 in MDA MB231 cells with IC50 = 106 nM.

Chemical Structure

UNC0642

CAS#1481677-78-4

Theoretical Analysis

MedKoo Cat#: 407288

Name: UNC0642

CAS#: 1481677-78-4

Chemical Formula: C29H44F2N6O2

Exact Mass: 546.3494

Molecular Weight: 546.71

Elemental Analysis: C, 63.71; H, 8.11; F, 6.95; N, 15.37; O, 5.85

Price and Availability

Size	Price	Availability
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
250mg	USD 1,350.00	Ready to ship
500mg	USD 2,950.00	Ready to ship
1g	USD 4,650.00	Ready to ship
2g	USD 6,450.00	Ready to ship

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Related CAS #

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Synonym

UNC0642, UNC-0642, UNC 0642

IUPAC/Chemical Name

2-(4,4-Difluoro-1-piperidinyl)-6-methoxy-N-[1-(1-methylethyl)-4-piperidinyl]-7-[3-(1-pyrrolidinyl)propoxy]-4-quinazolinamine

InChi Key

RNAMYOYQYRYFQY-UHFFFAOYSA-N

InChi Code

InChI=1S/C29H44F2N6O2/c1-21(2)36-14-7-22(8-15-36)32-27-23-19-25(38-3)26(39-18-6-13-35-11-4-5-12-35)20-24(23)33-28(34-27)37-16-9-29(30,31)10-17-37/h19-22H,4-18H2,1-3H3,(H,32,33,34)

SMILES Code

CC(N1CCC(NC2=C3C=C(OC)C(OCCCN4CCCC4)=CC3=NC(N5CCC(F)(F)CC5)=N2)CC1)C

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).

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# A21T05K17

QC Data

View QC data: current batch, Lot# A21T05K17

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

UNC0642 is a potent, selective inhibitor of histone methyltransferases G9a/GLP with IC50s less than 2.5 nM for G9a and GLP and shows more than 300-fold selective for G9a and GLP over a broad range of kinases, GPCRs, transporters, and ion channels.

In vitro activity:

UNC0642 is a novel inhibitor of G9a with high cellular potency and excellent selectivity in various cancer cell lines (Fig. 4a) and thus, was chosen for further targeting of G9a of UBC cells. UNC0642 was applied at different concentrations (ranging from 0 to 20 µM) to three human UBC cell lines (T24, J82, and 5637) for 72 h and it was found that UNC0642 reduced cell viability of all three lines in a dose-dependent manner based on an SRB assay (Fig. 4b). The IC50 values of UNC0642 in T24, J82, and 5637 cells were 9.85 ± 0.41 μM, 13.15 ± 1.72 μM, and 9.57 ± 0.37 μM, respectively. Western blotting analysis validated the specific decrease in the global level of histone H3K9me2 with UNC0642 treatment (Fig. 4c). A stable G9a-knockdown T24 cell line (shG9a) was constructed as a control to test whether pharmacological inhibition of G9a by UNC0642 was specific (Fig. S2a). It was found that T24 mock cells (shCTL) were more sensitive to UNC0642 than T24 shG9a cells (Fig. S2b), indicating that cell death induced by UNC0642 was partially dependent on G9a activity. To examine whether UNC0642 could induce apoptosis, Annexin V-FITC/PI double staining of UBC cell lines treated with UNC0642 was carried out (Fig. 5a). Flow cytometry analysis showed that the ratio of apoptotic cells was increased in a dose-dependent manner in three UBC cell lines (Fig. 5b). The expression levels of apoptosis markers, such as cleaved Caspase-3 and cleaved PARP, were consistently raised in UBC cells upon UNC0642 treatment according to western blotting analysis (Fig. 5c). Meanwhile, it was examined whether the expression of apoptosis-related genes, including Bim, Ampkα2, and ELL2, was also affected by UNC0642 treatment. The results revealed that the mRNA levels of the Ampkα2, ELL2, and Bim genes were upregulated in T24 cells treated with UNC0642 at concentrations of 10 μM and 20 μM (Fig. 5d), consistent with the siG9a treatment results (Fig. 3c). These results indicate that targeting of G9a with UNC0642 reduces cell viability and induces apoptosis in UBC cells. Reference: Acta Pharmacol Sin. 2019 Aug;40(8):1076-1084. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30765842/

In vivo activity:

To test the in vivo effects of G9a inhibition, J82 cells were subcutaneously injected into nude mice. One week after xenografts became palpable, UNC0642 (5 mg/kg) was administered via i.p. injection every other day for 11 days. UNC0642 inhibited tumor growth during the treatment window (P < 0.05; Fig. 6a) without a significant effect on body weight compared with the vehicle-treated group (Fig. 6b). At the endpoint of the experiment, xenografts were harvested, weighed, and processed for further IHC study. The average tumor weight in the UNC0642 group (1.15 g) was approximately half of that in the vehicle treatment group (2.30 g, P < 0.05; Fig. 6c, d). Moreover, IHC staining demonstrated that UNC0642 treatment strikingly decreased the histone H3K9me2 level in the nuclei of cancer cells in J82 xenografts (Fig. 6e). Ki67 (cell proliferation marker)-positive staining and cleaved Caspase 3 (apoptosis marker)-positive staining in cells were quantified (Fig. 6f, g). Targeting of G9a in vivo reduced cell proliferation (from 61.73% in the vehicle group to 22.20% in the UNC0642 group; P < 0.01) and induced apoptosis (from 0.36% in the vehicle group to 4.89% in the UNC0642 group; P < 0.05). In addition, the level of the proapoptotic protein BIM was increased in the UNC0642 treatment group, consistent with the in vitro data (Fig. 6h). Thus, targeting of G9a with UNC0642 suppressed UBC tumor growth and induced apoptosis in vivo. Reference: Acta Pharmacol Sin. 2019 Aug;40(8):1076-1084. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30765842/

	Solvent	mg/mL	mM	comments
Solubility
	DMSO	50.0	91.46

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 546.71 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:

In vitro protocol:

1. Cao YP, Sun JY, Li MQ, Dong Y, Zhang YH, Yan J, Huang RM, Yan X. Inhibition of G9a by a small molecule inhibitor, UNC0642, induces apoptosis of human bladder cancer cells. Acta Pharmacol Sin. 2019 Aug;40(8):1076-1084. doi: 10.1038/s41401-018-0205-5. Epub 2019 Feb 14. PMID: 30765842; PMCID: PMC6786297. 2. Liu F, Barsyte-Lovejoy D, Li F, Xiong Y, Korboukh V, Huang XP, Allali-Hassani A, Janzen WP, Roth BL, Frye SV, Arrowsmith CH, Brown PJ, Vedadi M, Jin J. Discovery of an in vivo chemical probe of the lysine methyltransferases G9a and GLP. J Med Chem. 2013 Nov 14;56(21):8931-42. doi: 10.1021/jm401480r. Epub 2013 Oct 31. PMID: 24102134; PMCID: PMC3880643.

In vivo protocol:

1. Cao YP, Sun JY, Li MQ, Dong Y, Zhang YH, Yan J, Huang RM, Yan X. Inhibition of G9a by a small molecule inhibitor, UNC0642, induces apoptosis of human bladder cancer cells. Acta Pharmacol Sin. 2019 Aug;40(8):1076-1084. doi: 10.1038/s41401-018-0205-5. Epub 2019 Feb 14. PMID: 30765842; PMCID: PMC6786297. 2. Kim Y, Lee HM, Xiong Y, Sciaky N, Hulbert SW, Cao X, Everitt JI, Jin J, Roth BL, Jiang YH. Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader-Willi syndrome. Nat Med. 2017 Feb;23(2):213-222. doi: 10.1038/nm.4257. Epub 2016 Dec 26. PMID: 28024084; PMCID: PMC5589073.

1: Sakai M, Masuda Y, Tarumoto Y, Aihara N, Tsunoda Y, Iwata M, Kamiya Y, Komorizono R, Noda T, Yusa K, Tomonaga K, Makino A. Genome-scale CRISPR-Cas9 screen identifies host factors as potential therapeutic targets for SARS-CoV-2 infection. iScience. 2024 Jul 8;27(8):110475. doi: 10.1016/j.isci.2024.110475. PMID: 39100693; PMCID: PMC11295705. 2: Singh J, Sah B, Shen Y, Liu L. Corrigendum to "Histone methyltransferase inhibitor UNC0642 promotes breast cancer cell death by upregulating TXNIP- dependent oxidative stress" [Chem. Biol. Interact. 385 (2023) 110720]. Chem Biol Interact. 2024 Aug 25;399:111136. doi: 10.1016/j.cbi.2024.111136. Epub 2024 Jul 16. Erratum for: Chem Biol Interact. 2023 Nov 1;385:110720. doi: 10.1016/j.cbi.2023.110720. PMID: 39018829. 3: Wang SE, Xiong Y, Jang MA, Park KS, Donahue M, Velez J, Jin J, Jiang YH. Newly developed oral bioavailable EHMT2 inhibitor as a potential epigenetic therapy for Prader-Willi syndrome. Mol Ther. 2024 Aug 7;32(8):2662-2675. doi: 10.1016/j.ymthe.2024.05.034. Epub 2024 May 24. PMID: 38796700; PMCID: PMC11405540. 4: Bernauer T, Nitsche V, Kaiser J, Gertzen CGW, Höfner G, Niessen KV, Seeger T, Steinritz D, Worek F, Gohlke H, Wanner KT, Paintner FF. Synthesis and biological evaluation of novel MB327 analogs as resensitizers for desensitized nicotinic acetylcholine receptors after intoxication with nerve agents. Toxicol Lett. 2024 Jun;397:151-162. doi: 10.1016/j.toxlet.2024.05.011. Epub 2024 May 15. PMID: 38759939. 5: Velez J, Han Y, Yim H, Yang P, Deng Z, Park KS, Kabir M, Kaniskan HÜ, Xiong Y, Jin J. Discovery of the First-in-Class G9a/GLP PROTAC Degrader. J Med Chem. 2024 Apr 25;67(8):6397-6409. doi: 10.1021/acs.jmedchem.3c02394. Epub 2024 Apr 11. PMID: 38602846; PMCID: PMC11069390. 6: Bellver-Sanchis A, Ávila-López PA, Tic I, Valle-García D, Ribalta-Vilella M, Labrador L, Banerjee DR, Guerrero A, Casadesus G, Poulard C, Pallàs M, Griñán- Ferré C. Neuroprotective effects of G9a inhibition through modulation of peroxisome-proliferator activator receptor gamma-dependent pathways by miR-128. Neural Regen Res. 2024 Nov 1;19(11):2532-2542. doi: 10.4103/1673-5374.393102. Epub 2024 Jan 8. PMID: 38526289; PMCID: PMC11090428. 7: De Clerck M, Manguin M, Henkous N, d'Almeida MN, Beracochea D, Mons N. Chronic alcohol-induced long-lasting working memory deficits are associated with altered histone H3K9 dimethylation in the prefrontal cortex. Front Behav Neurosci. 2024 Mar 1;18:1354390. doi: 10.3389/fnbeh.2024.1354390. PMID: 38495426; PMCID: PMC10941761. 8: Velez J, Han Y, Yim H, Yang P, Deng Z, Park KS, Kabir M, Kaniskan HÜ, Xiong Y, Jin J. Discovery of the First-in-class G9a/GLP PROTAC Degrader. bioRxiv [Preprint]. 2024 Feb 29:2024.02.26.582210. doi: 10.1101/2024.02.26.582210. Update in: J Med Chem. 2024 Apr 25;67(8):6397-6409. doi: 10.1021/acs.jmedchem.3c02394. PMID: 38464025; PMCID: PMC10925177. 9: Wang J, Zhang W, Xu H, Ellenbroek B, Dai J, Wang L, Yan C, Wang W. The Changes of Histone Methylation Induced by Adolescent Social Stress Regulate the Resting-State Activity in mPFC. Research (Wash D C). 2023 Oct 31;6:0264. doi: 10.34133/research.0264. PMID: 38434244; PMCID: PMC10907022. 10: Sichler S, Höfner G, Nitsche V, Niessen KV, Seeger T, Worek F, Paintner FF, Wanner KT. Screening for new ligands of the MB327-PAM-1 binding site of the nicotinic acetylcholine receptor. Toxicol Lett. 2024 Apr;394:23-31. doi: 10.1016/j.toxlet.2024.02.004. Epub 2024 Feb 20. PMID: 38387764. 11: Nitsche V, Höfner G, Kaiser J, Gertzen CGW, Seeger T, Niessen KV, Steinritz D, Worek F, Gohlke H, Paintner FF, Wanner KT. MS Binding Assays with UNC0642 as reporter ligand for the MB327 binding site of the nicotinic acetylcholine receptor. Toxicol Lett. 2024 Feb;392:94-106. doi: 10.1016/j.toxlet.2024.01.003. Epub 2024 Jan 10. PMID: 38216073. 12: Li P, Yan Z. An epigenetic mechanism of social isolation stress in adolescent female mice. Neurobiol Stress. 2023 Dec 18;29:100601. doi: 10.1016/j.ynstr.2023.100601. PMID: 38213831; PMCID: PMC10776430. 13: de Oliveira Filho RS, de Oliveira DA, Nisimoto MM, Marti LC. A Review of Advanced Cutaneous Melanoma Therapies and Their Mechanisms, from Immunotherapies to Lysine Histone Methyl Transferase Inhibitors. Cancers (Basel). 2023 Dec 8;15(24):5751. doi: 10.3390/cancers15245751. PMID: 38136297; PMCID: PMC10741407. 14: Singh J, Sah B, Shen Y, Liu L. Histone methyltransferase inhibitor UNC0642 promotes breast cancer cell death by upregulating TXNIP-dependent oxidative stress. Chem Biol Interact. 2023 Nov 1;385:110720. doi: 10.1016/j.cbi.2023.110720. Epub 2023 Sep 24. Erratum in: Chem Biol Interact. 2024 Aug 25;399:111136. doi: 10.1016/j.cbi.2024.111136. PMID: 37748637. 15: Crews FT, Fisher RP, Qin L, Vetreno RP. HMGB1 neuroimmune signaling and REST-G9a gene repression contribute to ethanol-induced reversible suppression of the cholinergic neuron phenotype. Mol Psychiatry. 2023 Dec;28(12):5159-5172. doi: 10.1038/s41380-023-02160-6. Epub 2023 Jul 4. PMID: 37402853; PMCID: PMC10764639. 16: Mereu E, Abbo D, Paradzik T, Cumerlato M, Bandini C, Labrador M, Maccagno M, Ronchetti D, Manicardi V, Neri A, Piva R. Euchromatic Histone Lysine Methyltransferase 2 Inhibition Enhances Carfilzomib Sensitivity and Overcomes Drug Resistance in Multiple Myeloma Cell Lines. Cancers (Basel). 2023 Apr 7;15(8):2199. doi: 10.3390/cancers15082199. PMID: 37190128; PMCID: PMC10137151. 17: Awada C, Bourgeois A, Lemay SE, Grobs Y, Yokokawa T, Breuils-Bonnet S, Martineau S, Krishna V, Potus F, Jeyaseelan J, Provencher S, Bonnet S, Boucherat O. G9a/GLP Targeting Ameliorates Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension. Am J Respir Cell Mol Biol. 2023 May;68(5):537-550. doi: 10.1165/rcmb.2022-0300OC. PMID: 36724371. 18: Ramos GP, Bamidele AO, Klatt EE, Sagstetter MR, Kurdi AT, Hamdan FH, Kosinsky RL, Gaballa JM, Nair A, Sun Z, Dasari S, Lanza IR, Rozeveld CN, Schott MB, Urrutia G, Westphal MS, Clarkson BD, Howe CL, Marietta EV, Luckey DH, Murray JA, Gonzalez M, Braga Neto MB, Gibbons HR, Smyrk TC, Johnsen S, Lomberk G, Faubion WA. G9a Modulates Lipid Metabolism in CD4 T Cells to Regulate Intestinal Inflammation. Gastroenterology. 2023 Feb;164(2):256-271.e10. doi: 10.1053/j.gastro.2022.10.011. Epub 2022 Oct 20. PMID: 36272457; PMCID: PMC9892272. 19: Park KS, Xiong Y, Yim H, Velez J, Babault N, Kumar P, Liu J, Jin J. Discovery of the First-in-Class G9a/GLP Covalent Inhibitors. J Med Chem. 2022 Aug 11;65(15):10506-10522. doi: 10.1021/acs.jmedchem.2c00652. Epub 2022 Jun 28. PMID: 35763668; PMCID: PMC9482816. 20: Zou J, Walter TJ, Barnett A, Rohlman A, Crews FT, Coleman LG Jr. Ethanol Induces Secretion of Proinflammatory Extracellular Vesicles That Inhibit Adult Hippocampal Neurogenesis Through G9a/GLP-Epigenetic Signaling. Front Immunol. 2022 May 13;13:866073. doi: 10.3389/fimmu.2022.866073. PMID: 35634322; PMCID: PMC9136051.