In vitro: UNC0642 is competitive with the peptide substrate and non-competitive with the cofactor SAM. The Ki of UNC0642 is determined to be 3.7 ± 1 nM. It is more than 20,000-fold selective for G9a and GLP over 13 other methyltransferases (IC50 > 50,000 nM) and more than 2,000-fold selective over PRC2-EZH2 (IC50 > 5,000 nM). UNC0642 displays high potency (IC50 < 150 nM) in reducing cellular levels of H3K9me2, low cell toxicity (EC50 > 3,000 nM), resulting in a good separation of functional potency and cell toxicity with a tox/function ratio (which is determined by dividing the EC50 value of the observed toxicity by the IC50 value of the functional potency) of > 45 in U2OS, PC3, and PANC-1 cells. UNC0642 reduces clonogenicity in PANC-1 cells in a concentration-dependent manner while it has no effect on clonogenicity in MDA-MB-231 cells.
In vivo: For evaluation in vivo PK properties in male Swiss Albino mice, a single intraperitoneal (IP) injection (5 mg/kg) of UNC0642 results in a plasma Cmax (maximum concentration) of 947 ng/mL and an AUC (area under the curve) of 1265 hr*ng/mL. It displays modest brain penetration with a brain/plasma ratio of 0.33. A single intraperitoneal (i.p.) injection dose of 5 mg/kg of UNC0642 is sufficient to inhibit G9a activity in adult mice. UNC0642 improves the life span and weight gain of m+/pΔS−U pups, produces long-lasting activation of PWS-associated genes, is apparently well tolerated and produces no notable acute toxicity, and does not interfere with the expression of the AS-associated Ube3a gene.
| Cell Experiment | |
|---|---|
| Cell lines | MDA-MB-231, PC3, and U2OS cells |
| Preparation method | MDA-MB-231, PC3, and U2OS cells are cultured in RPMI with 10% FBS, PANC-1 cells in DMEM with 10% FBS. Cells are treated with inhibitors for 48 h. Cell viability assays are performed by incubating cells with 0.1 mg/mL of resazurin for 3-4 h. Resazurin reduction is monitored with 544 nm excitation, measuring fluorescence at 590 nm. |
| Concentrations | |
| Incubation time | 48 h |
| Animal Experiment | |
|---|---|
| Animal models | male Swiss Albino mice |
| Formulation | |
| Dosages | 5 mg/kg |
| Administration | i.p. |
| Molecular Weight | 546.7 |
| Formula | C29H44F2N6O2 |
| CAS Number | 1481677-78-4 |
| Solubility (25°C) | 1481677-78-4 |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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