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Purity: ≥98%
UNC0642 (UNC-0642) is a novel, potent, selective, dual inhibitor of G9a/GLP (histone methyltransferases) with antitumor activity. It inhibits G9a and GLP with IC50 values of < 2.5 nM. UNC0642 exhibits more than 300-fold selectivity for G9a and GLP over a broad range of kinases, GPCRs, transporters, and ion channels. UNC0642 has better pharmacokinetic properties than its early generations (lead compounds). As the first G9a and GLP in vivo chemical probe, UNC0642 not only maintains high in vitro and cellular potency, low cell toxicity, and excellent selectivity, but also displays improved in vivo PK properties, making it suitable for animal studies.
| Targets |
UNC0642 targets lysine methyltransferases G9a (EHMT2) and GLP (EHMT1) [1]
UNC0642 targets EHMT2 [2] |
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| ln Vitro |
UNC0642 exhibits good selectivity, low cytotoxicity, and great in vitro and cellular potency. UNC0642 does not compete with the cofactor SAM; instead, it competes with the peptide substrate. It was found that UNC0642's Ki was 3.7±1 nM. Like G9a, UNC0642 has strong in vitro potency (IC50< 2.5 nM) against GLP. For G9a and GLP, UNC0642 exhibits > 300-fold selectivity across a wide variety of kinases, GPCRs, transporters, and ion channels. In several cell lines, UNC0642 shows strong separation of functional potency and cytotoxicity, minimal cytotoxicity, and great potency in lowering the H3K9me2 mark. It lessens the PANC-1 cell line's capacity to proliferate into pancreatic cancer [1].
1. UNC0642 maintains high in vitro potency and excellent selectivity against G9a/GLP, with a separation of functional potency and cell toxicity (consistent with the cellular probe UNC0638, which is structurally/functionally related to UNC0642) [1] 2. In EGFR-TKI-resistant NSCLC cells (PC9/ER, HCC827/ER), inhibition of EHMT2 by UNC0642 (related to UNC0638 with the same target) leads to upregulation of PTEN expression (detected by Western blot and real-time RT-PCR), downregulation of p-AKT levels, inhibition of cell migration and tumor sphere formation, and enhancement of sensitivity to Erlotinib; EHMT2 expression and enzymatic activity are elevated in EGFR-TKI-resistant NSCLC cells compared to parental cells [2] 3. UNC0642 (as an EHMT2 inhibitor) significantly inhibits cell growth and induces apoptosis in EGFR-TKI-resistant NSCLC cells, as evidenced by increased cleaved PARP (Clv-PARP) expression; genetic knockdown of EHMT2 also enhances TKI sensitivity in resistant cells [2] 4. ChIP assays show that UNC0642-mediated EHMT2 inhibition reduces H3K9Me2 enrichment at the PTEN gene promoter/enhancer regions (P1, P2, P3, P4) in PC9/ER cells, reversing PTEN transcriptional repression [2] |
| ln Vivo |
AUC (area under the curve) *ng/mL of 1265 hours and a plasma Cmax (maximum concentration) of 947 ng/mL were obtained from a single intraperitoneal (IP) injection (5 mg/kg) of UNC0642 [1].
1. In a preclinical EGFR-TKI-resistant NSCLC xenograft model (PC9/ER cells implanted in mice), treatment with UNC0642 alone or in combination with Erlotinib significantly reduces relative tumor volumes and tumor weights (P < 0.01 vs control; combined treatment shows better efficacy than UNC0642 monotherapy, P < 0.05); no significant changes in mouse body weights were observed [2] 2. Western blot analysis of tumor tissues from UNC0642-treated xenografts shows decreased H3K9Me2 levels, increased PTEN expression, and reduced p-AKT levels, confirming the regulation of the PTEKT signaling pathway in vivo [2] 3. UNC0642 is the first in vivo chemical probe for G9a/GLP, with improved in vivo PK properties suitable for animal studies [1] |
| Enzyme Assay |
1. For the functional characterization of G9a/GLP inhibitors (including the precursor of UNC0642, inhibitor 7), competition assays with H3K9 peptide substrate were performed: the apparent K m of the peptide increased linearly with inhibitor concentration, confirming competitive binding with the peptide substrate; competition assays with cofactor SAM showed that the apparent K m of SAM was unaffected by inhibitor concentration, indicating non-competitive binding with SAM [1]
2. Selectivity assays were conducted for inhibitor 7 (precursor of UNC0642) against 15 other methyltransferases to evaluate the specific inhibitory effect on G9a/GLP [1] 3. Enzymatic activity assays of EHMT2 in EGFR-TKI-resistant and parental NSCLC cell lysates were performed to measure H3K9Me, H3K9Me2, and H3K27Me3 levels (Histone-3 as loading control), confirming elevated EHMT2 activity in resistant cells [2] |
| Cell Assay |
1. Clonogenic assays were performed on PANC-1 and MDA-MB-231 cells treated with inhibitor 7 (precursor of UNC0642) at 0, 0.5, or 1 µM for 2 weeks: inhibitor 7 significantly reduced colony formation in PANC-1 cells but had no effect on MDA-MB-231 cells, with quantitative graphical analysis of colony numbers [1]
2. Cell viability assays: PC9/ER cells were treated with UNC0642 (or EHMT2 siRNA) combined with different concentrations of Erlotinib for 48 h; cell viability was measured to assess TKI sensitivity (scramble siRNA/DMSO as control) [2] 3. Apoptosis assays: PC9/ER and PC9 cells with PTEN gene manipulation were treated with Erlotinib (0.1 μM for PC9, 1 μM for PC9/ER) for 48 h; Annexin V/PI double staining was used to detect apoptosis (scramble siRNA/mock vector as control) [2] 4. Cell migration assays: PC9, PC9/ER cells were treated with 100 nM UNC0638 (analog of UNC0642) or 20 nM EHMT2 siRNA; migration capacity was measured (scramble siRNA/DMSO as control) [2] 5. Tumor sphere formation assays: HCC827, HCC827/ER cells were treated with 100 nM UNC0638 (analog of UNC0642) or 20 nM EHMT2 siRNA; tumor sphere numbers were counted (scale bars, 100 μm; scramble siRNA/DMSO as control) [2] 6. Western blot assays: EGFR-TKI-resistant (PC9/ER, HCC827/ER) and parental cells were lysed to detect EHMT2, EHMT1, H3K9Me, H3K9Me2, H3K27Me3, p-AKT, AKT, nuclear p65, nuclear β-Catenin, nuclear Gli1, nuclear YAP, PTEN, TBK1, TRAF6, TRAF4, PP2A, and cleaved PARP levels (β-actin/Histone-3 as loading control) [2] 7. Real-time RT-PCR assays: EGFR-TKI-resistant cells treated with UNC0642 or EHMT2 siRNA were used to detect PTEN, Bcl-2, and VEGF mRNA expression levels (GAPDH as control) [2] 8. ChIP assays: Chromatin was extracted from PC9 and PC9/ER cells, immunoprecipitated with H3K9Me2 antibody, and quantitative PCR was performed to measure H3K9Me2 binding to PTEN gene promoter/enhancer regions (P1-P4) [2] |
| Animal Protocol |
5 mg/kg; .i.p.
Male Swiss Albino mice 1. For EGFR-TKI-resistant NSCLC xenograft model: PC9/ER cells were subcutaneously implanted into mice; when tumors formed, mice were randomized into groups treated with UNC0642, Erlotinib, or the combination; tumor volumes and weights were measured regularly, and body weights were monitored to assess toxicity; after treatment, tumor tissues were collected for Western blot analysis [2] 2. UNC0642 was developed as an in vivo chemical probe with improved PK properties for animal studies [1] |
| ADME/Pharmacokinetics |
1. Compared with UNC0638 (which has poor pharmacokinetic (PK) characteristics and is not suitable for animal studies), UNC0642 has better pharmacokinetic characteristics, making it suitable for in vivo experiments [1]
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| Toxicity/Toxicokinetics |
1. UNC0642 maintained low cytotoxicity (consistent with UNC0638, which showed excellent performance in both functional activity and cytotoxicity)[1]
2. In PC9/ER xenograft studies, UNC0642 treatment (alone or in combination with erlotinib) did not cause significant changes in mouse body weight, indicating no obvious acute toxicity[2] |
| References | |
| Additional Infomation |
1. UNC0642 is the first in vivo chemical probe for lysine methyltransferases G9a (EHMT2) and GLP (EHMT1). Its development aims to address the poor pharmacokinetic properties of the cell probe UNC0638 while maintaining high efficiency, low toxicity, and excellent selectivity [1]. 2. G9a/GLP catalyzes monomethylation and dimethylation of histone H3 lysine 9 (H3K9me2) and non-histone proteins, which are associated with various human diseases. UNC0642 can be used to test the biological/disease hypothesis of G9a/GLP in animal models [1]. 3. UNC0642 reverses EGFR-TKI resistance in NSCLC by epigenetic regulation of the PTEKT signaling pathway: EHMT2 mediates PTEN transcriptional repression through H3K9Me2 modification, leading to AKT pathway activation and TKI reversal. Drug resistance; high EHMT2 expression combined with low PTEN expression predicts poor overall survival in NSCLC patients [2]
4. UNC0642 (as an EHMT2 inhibitor) in combination with erlotinib showed enhanced antitumor activity in EGFR-TKI resistant NSCLC, indicating that EHMT2 is a potential clinical target for drug-resistant NSCLC [2] |
| Molecular Formula |
C29H44F2N6O2
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|---|---|---|
| Molecular Weight |
546.7
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| Exact Mass |
546.349
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| Elemental Analysis |
C, 63.71; H, 8.11; F, 6.95; N, 15.37; O, 5.85
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| CAS # |
1481677-78-4
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| Related CAS # |
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| PubChem CID |
53315878
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
679.2±65.0 °C at 760 mmHg
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| Flash Point |
364.6±34.3 °C
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| Vapour Pressure |
0.0±2.1 mmHg at 25°C
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| Index of Refraction |
1.592
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| LogP |
3.3
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
39
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| Complexity |
739
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1(C([H])([H])C([H])([H])N(C2=NC3=C([H])C(=C(C([H])=C3C(=N2)N([H])C2([H])C([H])([H])C([H])([H])N(C([H])(C([H])([H])[H])C([H])([H])[H])C([H])([H])C2([H])[H])OC([H])([H])[H])OC([H])([H])C([H])([H])C([H])([H])N2C([H])([H])C([H])([H])C([H])([H])C2([H])[H])C([H])([H])C1([H])[H])F
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| InChi Key |
RNAMYOYQYRYFQY-UHFFFAOYSA-N
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| 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)
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| Chemical Name |
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.57 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.57 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.57 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8292 mL | 9.1458 mL | 18.2916 mL | |
| 5 mM | 0.3658 mL | 1.8292 mL | 3.6583 mL | |
| 10 mM | 0.1829 mL | 0.9146 mL | 1.8292 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
MOA studies of inhibitor7(UNC0642).J Med Chem. 2013 Nov 14; 56(21): 10.1021/jm401480r. |
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Selectivity of inhibitor7(UNC0642)versus 15 other methyltransferases.J Med Chem. 2013 Nov 14; 56(21): 10.1021/jm401480r. |
Inhibitor7(UNC0642)affects clonogenicity of PANC-1 cells but not MDA-MB-231 cells.J Med Chem. 2013 Nov 14; 56(21): 10.1021/jm401480r. |
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