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The ClpP activator ONC‐212 (TR‐31), a fluorinated-ONC201 analogue, is broadly efficacious across most solid tumors and hematological malignancies in the low nanomolar range and has robust anti-leukemic activity.
In vitro: ONC212 shows an anti-proliferative effect in a large panel of pancreatic cancer cell lines with ONC212 having at least a ten-fold increased potency than ONC201. ONC212 induces apoptosis earlier and at lower concentrations than ONC201 in sensitive pancreatic cancer cell lines. ONC212 exerts potent and prominent apoptogenic effects on acute myeloid leukemia (AML) and mantle cell lymphoma (MCL) cell lines (e.g., ED50s of 141.0 nM in p53 wild-type OCI-AML3 cells, 105.7 nM in MOLM13 cells, and 265.2 nM in p53-null JeKo-1 cell lines). Time course analysis of apoptosis in OCI-AML3 cells shows that ONC212 takes more than 36 hours to start to induce apoptosis. ONC212 significantly induces Sub-G1 apoptotic cells and/or cell cycle arrest.
In vivo: ONC212 shows improved efficacy in melanoma and hepatocellular carcinoma xenograft models. ONC212 has a broad therapeutic window, an acceptable PK profile, and is orally well-tolerated in mice with no evidence of toxicity at efficacious doses in both colon and triple negative breast cancer. ONC212 exhibits rapid kinetics of activity. ONC212 has a slightly shorter half-life than ONC201, with a clearance from the blood at 12 hours, T1/2 of 4.3 hours, and Cmax of 1.4 mg/mL. It has a prolonged pharmacodynamic effect despite systemic clearance. Oral ONC212 shows potent anti-tumor efficacy in a human melanoma xenograft and hepatocellular model. ONC206 and ONC201 both inhibit invasion and migration of tumor cells while ONC212 inhibits only invasion.
| Cell Experiment | |
|---|---|
| Cell lines | PANC-1 and HPAF-Ⅱ cells |
| Preparation method | Colony formation assays are performed by seeding 0.2 × 10^6 cells/well in a 6-well plate and treatment with indicated doses of ONC201 or ONC212. At 72 hours post-treatment, cells are harvested and 500 cells per treatment group are plated in drug-free media in triplicate for colony formation. Colonies are stained with 0.25% crystal violet on Day 10, imaged, counted and reported as number of colonies ± SEM. |
| Concentrations | 5 µM or 20 µM |
| Incubation time | 72 h |
| Animal Experiment | |
|---|---|
| Animal models | PANC-1, Capan-2, HPAF-II and BxPC3 xenograft models (athymic nu/nu mice) |
| Formulation | 10% DMSO, 20% Kolliphor EL (Sigma), 70% PBS |
| Dosages | 50 mg/kg |
| Administration | oral gavage |
| Molecular Weight | 440.46 |
| Formula | C24H23F3N4O |
| CAS Number | 1807861-48-8 |
| Solubility (25°C) | DMSO 45 mg/mL (ultrasonic) |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
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