MI-503 is a potent and selective Menin-MLL inhibitor with IC50 of 14.7 nM. MI-503 shows pronounced growth suppressive activity in a panel of human MLL leukemia cell lines(GI50 at 250 nM-570 nM range), but only a minimal effect in human leukemia cell lines without MLL translocations. MI-503 is also very effective in inducing differentiation of MLL leukemia cells and substantially increases expression of CD11b, a myeloid differentiation marker. These effects are accompanied by reduced c-kit (CD117) expression, a marker associated with leukemia stem cells (LSCs).
In vivo, MI-503 blocks hematologic tumors in vivo and reduces MLL leukemia tumor burden. MI-503 achieves high level in peripheral blood following a single intravenous or oral dose, while also showing high oral bioavailability (~75%). Prolonged treatment (38 days) with MI-503 induces no toxicity in mice as reflected by no alterations in the body weight and no morphological changes in liver and kidney tissues.
Molecular Weight | 564.63 |
Formula | C28H27F3N8S |
CAS Number | 1857417-13-0 |
Solubility (25°C) | DMSO: ≥ 50 mg/mL |
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.
[2] Laurie K Svoboda, et al. Menin regulates the serine biosynthetic pathway in Ewing sarcoma
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