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| Targets |
M4205 targets multiple receptor tyrosine kinases with the following IC50 values: PDGFRB (2.6 nM), CSF1R (5.5 nM), c-Kit (44 nM), PDGFRA (50 nM), FLT3 (141 nM), and LCK (141 nM). The compound shows particularly high activity against c-KIT mutants, including those with mutations in exons 11, 13, and 17. M4205 potently inhibits KIT autophosphorylation in both imatinib-sensitive and imatinib-resistant GIST cell lines. The kinase selectivity profile of M4205 is superior to that of approved KIT inhibitors including imatinib, sunitinib, regorafenib, and ripretinib. M4205 shows only weak cellular inhibition of CSF1R autophosphorylation with an IC50 of 952 nM in THP-1 cells, indicating that its primary activity is directed toward KIT rather than CSF1R. This high selectivity for KIT over other kinases contributes to its favorable safety profile.
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| ln Vitro |
In vitro, M4205 potently inhibits KIT autophosphorylation in imatinib-sensitive GIST430 cells with an IC50 of 4 nM, and in imatinib-resistant GIST430/654 cells with an IC50 of 48 nM. It also inhibits KIT phosphorylation in AML Kasumi-1 cells with an IC50 of 4 nM. M4205 demonstrates high activity against c-KIT exon 11, 13, and 17 mutations, including the clinically relevant V654A mutation with an IC50 of 10 nM. The compound inhibits cell proliferation in GIST cell lines with EC50 values in the low nanomolar range. In cellular assays, M4205 shows dose-dependent inhibition of KIT signaling pathways, including downstream effectors such as STAT3, AKT, and ERK. The compound demonstrates excellent cellular permeability and maintains its inhibitory activity in the presence of serum proteins, which is important for predicting in vivo efficacy.
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| ln Vivo |
In vivo, M4205 exhibits significant antitumor efficacy in GIST xenograft mouse models. In GIST430/654 xenograft models expressing exon 11 mutations, M4205 delivered strong antitumor responses compared with imatinib. In xenograft models expressing secondary resistance mutations in exon 13, M4205 produced deeper antitumor responses than sunitinib, the standard second-line treatment. Similar results were observed in xenograft models with exon 17 secondary resistance mutations. M4205 demonstrates dose-dependent antitumor activity in these models, with tumor growth inhibition observed at clinically relevant doses. The compound is orally bioavailable and exhibits favorable pharmacokinetic properties that support once-daily dosing. M4205 is well-tolerated at efficacious doses in preclinical studies.
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| Enzyme Assay |
Kinase inhibition is measured using biochemical assays with recombinant kinases and ATP. In these assays, compounds are incubated with the kinase of interest, a peptide substrate, and ATP; phosphorylation of the substrate is detected by HTRF (homogeneous time-resolved fluorescence) or luminescence-based methods. IC50 values are calculated from dose-response curves generated using varying concentrations of the test compound. Selectivity profiling is performed by screening M4205 against a panel of kinases to assess off-target inhibition. Binding kinetics, including association and dissociation rates, may also be characterized to understand the mechanism of inhibition. These biochemical assays are essential for determining the potency and selectivity of M4205 against its intended targets.
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| Cell Assay |
M4205 is tested on a panel of GIST cell lines (GIST430, GIST430/654, GIST882) and AML Kasumi-1 cells. Cells are treated with M4205 at varying concentrations for 24-72 hours; KIT phosphorylation is assessed by Western blot or ELISA using phospho-specific antibodies; cell proliferation is measured by MTT, CellTiter-Glo, or colony formation assays. Apoptosis is evaluated by flow cytometry using Annexin V staining or by measuring caspase activity. The compound's ability to overcome imatinib resistance is assessed by comparing its activity in imatinib-sensitive versus imatinib-resistant cell lines. These cellular assays provide critical information on the potency, efficacy, and mechanism of action of M4205 in relevant disease models.
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| Animal Protocol |
Female athymic mice bearing GIST xenografts (GIST430, GIST430/654, or patient-derived xenografts) are orally administered M4205 at varying doses (e.g., 35 mg/kg daily) for up to 30 days. Tumor volume is measured twice weekly using calipers; body weight and clinical signs are monitored throughout the study. Endpoints include tumor growth inhibition (TGI), tumor regression, histopathological analysis of tumors, and evaluation of KIT phosphorylation in tumor tissue. Pharmacokinetic-pharmacodynamic (PK-PD) relationships are established by correlating plasma drug concentrations with target inhibition and antitumor efficacy. These xenograft studies are critical for demonstrating the in vivo activity of M4205 and supporting its clinical development.
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| ADME/Pharmacokinetics |
M4205 has favorable oral bioavailability, metabolic stability, and permeability, supporting once-daily oral dosing. Preclinical data indicate good systemic exposure and target coverage in xenograft models at clinically relevant doses. The compound exhibits low clearance and moderate volume of distribution, consistent with once-daily dosing. Detailed pharmacokinetic parameters are proprietary but indicate that M4205 achieves sufficient plasma concentrations to inhibit KIT phosphorylation throughout the dosing interval. The favorable pharmacokinetic profile of M4205 is attributed to its excellent physicochemical properties, including high solubility and permeability. Food effects on absorption have been evaluated in preclinical models to inform clinical dosing recommendations.
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| Toxicity/Toxicokinetics |
In preclinical studies, M4205 is well-tolerated at efficacious doses, with no severe toxicities reported in animal models at the doses tested. The safety profile is consistent with that of other kinase inhibitors; off-target effects are minimal due to the compound's high kinase selectivity. Common adverse effects observed with kinase inhibitors, such as gastrointestinal disturbances, myelosuppression, and hepatotoxicity, are expected to be less frequent with M4205 due to its selective targeting of KIT. The high selectivity of M4205 for KIT over CSF1R and other kinases contributes to its favorable safety profile. Long-term toxicity studies and carcinogenicity assessments are typically conducted as part of the preclinical development program to support clinical use.
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| References | |
| Additional Infomation |
IDRX-42, a KIT mutant inhibitor, is a small molecule inhibitor with high oral bioavailability that inhibits various mast cell/stem cell factor receptor KIT (c-Kit; SCFR) mutants, exhibiting potential antitumor activity. After oral administration, IDRX-42 targets, binds to, and inhibits specific c-Kit mutants. This may inhibit the proliferation of cancer cells overexpressing these c-Kit mutants. c-Kit is a transmembrane protein and receptor tyrosine kinase (RTK) that is overexpressed in various solid tumors and hematologic malignancies, playing a crucial role in the regulation of cell differentiation and proliferation. c-Kit mutants are commonly associated with tumor chemotherapy resistance.
M4205 (Velzatinib, IDRX-42) was initially discovered by Merck KGaA and is being developed by IDRx for gastrointestinal stromal tumors (GISTs) driven by c-KIT mutations. The compound has received FDA Fast Track designation and is in clinical development for GIST, particularly for patients who have failed or are intolerant to prior KIT inhibitors. M4205 is designed to overcome common resistance mutations in KIT, including those in exons 13 and 17, which are associated with progression on imatinib and sunitinib. Clinical trials are evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of M4205 in patients with advanced GIST. The compound represents a promising new therapy for patients with KIT-mutant GIST who have limited treatment options after progression on existing therapies. |
| Molecular Formula |
C29H32N8O
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|---|---|
| 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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