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M4205 (M-4205) is a highly selective inhibitor of disease-relevant cKIT mutations for unresectable metastatic or recurrent gastrointestinal stromal tumors (GIST). It had high activity against exon 11, 13 and 17 mutations of cKIT, with high kinase selectivity, with excellent metabolic stability, permeability, and solubility. Preclinical studies of M4205 in GIST xenograft models expressing mutations in exon 11 showed that M4205 delivered strong responses compared with imatinib. Compared with second-line standard of care sunitinib, M4205 treatment resulted in deeper anti-tumor response in xenograft models expressing secondary resistance mutations in exon 13. Similar results were seen in a xenograft model expressing secondary resistance mutations in exon 17. M4205 has the potential to become a best-in-class option for GIST. There is a phase I clinical study of GIST in preparation.
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| Additional Infomation |
KIT-mutant Inhibitor IDRX-42 is an orally bioavailable small molecule inhibitor of multiple mutated forms of mast/stem cell factor receptor KIT (c-Kit; SCFR), with potential antineoplastic activity. Upon oral administration, KIT-mutant inhibitor IDRX-42 targets, binds to and inhibits specific c-Kit mutants. This may inhibit tumor cell proliferation in cancer cell types that overexpress these c-Kit mutations. c-Kit, a transmembrane protein and receptor tyrosine kinase (RTK) overexpressed in various solid tumors and hematological malignancies, plays a key role in the regulation of cell differentiation and proliferation. Mutant forms of c-Kit are often associated with tumor chemoresistance.
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| Molecular Formula |
C29H32N8O
|
|---|---|
| Molecular Weight |
508.6174
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| Exact Mass |
508.269
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| CAS # |
2590556-80-0
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| Related CAS # |
2590556-80-0;
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| PubChem CID |
155587867
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| Appearance |
Solid powder
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| LogP |
4.3
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
38
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| Complexity |
715
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O(C1C([H])=C([H])N2C(C3=C([H])C(=NC([H])=N3)N([H])C([H])([H])C3C([H])=C([H])C(=C([H])C=3[H])C3C([H])=NN(C([H])([H])[H])C=3[H])=C([H])N=C2C=1[H])C([H])([H])C([H])([H])C([H])([H])N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H]
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| InChi Key |
LVMAULGVWBINFP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C29H32N8O/c1-35-20-24(18-34-35)23-7-5-22(6-8-23)17-30-28-16-26(32-21-33-28)27-19-31-29-15-25(9-13-37(27)29)38-14-4-12-36-10-2-3-11-36/h5-9,13,15-16,18-21H,2-4,10-12,14,17H2,1H3,(H,30,32,33)
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| Chemical Name |
N-[[4-(1-methylpyrazol-4-yl)phenyl]methyl]-6-[7-(3-pyrrolidin-1-ylpropoxy)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-amine
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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 |
| 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) |
DMSO : ~5 mg/mL (~9.83 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.11 mg/mL (2.18 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 11.1 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: ≥ 1.11 mg/mL (2.18 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 11.1 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9661 mL | 9.8305 mL | 19.6610 mL | |
| 5 mM | 0.3932 mL | 1.9661 mL | 3.9322 mL | |
| 10 mM | 0.1966 mL | 0.9831 mL | 1.9661 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.
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