I-0436650
I-0436650 is an orally active SHP2 inhibitor with an IC50 of 4 nM and a Kd value of 0.3 nM. I-0436650 binds allosterically to the channel between the C-SH2, N-SH2 and PTP catalytic domains, locking the protein in an inactive closed conformation. I-0436650 potently inhibits ERK phosphorylation and suppresses MAPK pathway activity. I-0436650 exhibits antiproliferative activity in EGFR- and RAS-dependent cells. I-0436650 can be used in the research of RAS-driven cancers, EGFR-mutated cancers and RTK-driven cancers.
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- CAS No.: 2843690-50-4
- Formule: C22H22ClN9S
- Masse moléculaire:479.99
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
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Activité biologique
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Activité biologique
Description
IC50 & Target
[1]|
SHP2 4 nM (IC50) |
SHP2 0.3 nM (Kd) |
ERK |
p38 MAPK |
EGFR |
Ras |
RTK |
Cellular Effect
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Cell Line
|
Type | Value | Description | References |
|---|---|---|---|---|
| KYSE-520 cell line | IC50 |
13 nM
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Inhibition of ERK phosphorylation in human EGFR-amplified esophageal squamous cell carcinoma KYSE-520 cells.
Inhibition of ERK phosphorylation in human EGFR-amplified esophageal squamous cell carcinoma KYSE-520 cells.
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42593923 |
| KYSE-520 cell line | IC50 |
216 nM
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Antiproliferative activity against human EGFR-amplified esophageal squamous cell carcinoma KYSE-520 cells.
Antiproliferative activity against human EGFR-amplified esophageal squamous cell carcinoma KYSE-520 cells.
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42593923 |
| NCI-H358 | IC50 |
199 nM
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Antiproliferative activity against human KRASG12C mutant NCI-H358 cells assessed as reduction in cell viability after 6-day incubation using a luminescence-based assay.
Antiproliferative activity against human KRASG12C mutant NCI-H358 cells assessed as reduction in cell viability after 6-day incubation using a luminescence-based assay.
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42593923 |
| SW837 | IC50 |
367 nM
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Antiproliferative activity against human KRASG12C mutant SW 837 cells assessed as reduction in cell viability after 6-day incubation using a luminescence-based assay.
Antiproliferative activity against human KRASG12C mutant SW 837 cells assessed as reduction in cell viability after 6-day incubation using a luminescence-based assay.
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42593923 |
| SW1463 | IC50 |
14 nM
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Antiproliferative activity against human KRASG12C mutant SW 1463 cells assessed as reduction in cell viability after 6-day incubation using a luminescence-based assay.
Antiproliferative activity against human KRASG12C mutant SW 1463 cells assessed as reduction in cell viability after 6-day incubation using a luminescence-based assay.
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42593923 |
| NCI-H1975 | IC50 |
261 nM
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Antiproliferative activity against human EGFR T790M L858R mutant NCI-H1975 cells assessed as reduction in cell viability after 6-day incubation using a luminescence-based assay.
Antiproliferative activity against human EGFR T790M L858R mutant NCI-H1975 cells assessed as reduction in cell viability after 6-day incubation using a luminescence-based assay.
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42593923 |
| HCC827 | IC50 |
101 nM
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Antiproliferative activity against human EGFR deletion mutant NCI-HCC827 cells assessed as reduction in cell viability after 6-day incubation using a luminescence-based assay.
Antiproliferative activity against human EGFR deletion mutant NCI-HCC827 cells assessed as reduction in cell viability after 6-day incubation using a luminescence-based assay.
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42593923 |
| NCI-N87 | IC50 |
25 nM
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Antiproliferative activity against human RTK mutant NCI-N87 cells assessed as reduction in cell viability after 6-day incubation using a luminescence-based assay.
Antiproliferative activity against human RTK mutant NCI-N87 cells assessed as reduction in cell viability after 6-day incubation using a luminescence-based assay.
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42593923 |
| NCI-H358 | IC50 |
61 nM
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Inhibition of ERK phosphorylation in human KRASG12C mutant NCI-H358 cells after 6-hour incubation quantified using an electrochemiluminescence assay.
Inhibition of ERK phosphorylation in human KRASG12C mutant NCI-H358 cells after 6-hour incubation quantified using an electrochemiluminescence assay.
|
42593923 |
| SW837 | IC50 |
58 nM
|
Inhibition of ERK phosphorylation in human KRASG12C mutant SW 837 cells after 6-hour incubation quantified using an electrochemiluminescence assay.
Inhibition of ERK phosphorylation in human KRASG12C mutant SW 837 cells after 6-hour incubation quantified using an electrochemiluminescence assay.
|
42593923 |
| SW1463 | IC50 |
25 nM
|
Inhibition of ERK phosphorylation in human KRASG12C mutant SW 1463 cells after 6-hour incubation quantified using an electrochemiluminescence assay.
Inhibition of ERK phosphorylation in human KRASG12C mutant SW 1463 cells after 6-hour incubation quantified using an electrochemiluminescence assay.
|
42593923 |
| NCI-H1975 | IC50 |
65 nM
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Inhibition of ERK phosphorylation in human EGFR T790M L858R mutant NCI-H1975 cells after 6-hour incubation quantified using an electrochemiluminescence assay.
Inhibition of ERK phosphorylation in human EGFR T790M L858R mutant NCI-H1975 cells after 6-hour incubation quantified using an electrochemiluminescence assay.
|
42593923 |
| HCC827 | IC50 |
41 nM
|
Inhibition of ERK phosphorylation in human EGFR deletion mutant NCI-HCC827 cells after 6-hour incubation quantified using an electrochemiluminescence assay.
Inhibition of ERK phosphorylation in human EGFR deletion mutant NCI-HCC827 cells after 6-hour incubation quantified using an electrochemiluminescence assay.
|
42593923 |
| NCI-N87 | IC50 |
48 nM
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Inhibition of ERK phosphorylation in human RTK mutant NCI-N87 cells after 6-hour incubation quantified using an electrochemiluminescence assay.
Inhibition of ERK phosphorylation in human RTK mutant NCI-N87 cells after 6-hour incubation quantified using an electrochemiluminescence assay.
|
42593923 |
In Vitro
I-0436650 potently and selectively inhibits full-length human wild-type and mutant SHP2 proteins, with no activity against the isolated SHP2-PTP catalytic domain or human SHP1, confirming its allosteric mechanism of action[1].
I-0436650 tightly binds to human SHP2 with low nanomolar affinity and a very slow dissociation rate, resulting in an extended residence time on the target[1].
I-0436650 inhibits MAPK pathway signaling (measured by pERK) and proliferation in KYSE-520 cells with low nanomolar and submicromolar potency, respectively[1].
I-0436650 (1 pM-10 mM; 6 days) exhibits broad antiproliferative activity across genetically diverse KRAS-, EGFR-, and RTK-driven human cancer cell lines, with varying potency reflecting underlying oncogenic drivers[1].
I-0436650 (1 pM-10 mM; 6 hours) effectively inhibits MAPK pathway signaling via suppression of ERK phosphorylation in KRAS-, EGFR-, and RTK-driven human cancer cell lines after 6 hours of treatment[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:Human KRASG12C mutant NCI-H358, SW 837, SW 1463 cells; human EGFR T790M L858R mutant NCI-H1975 cells; human EGFR deletion mutant NCI-HCC827 cells; human RTK mutant NCI-N87 cells
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Concentration:1 pM-10 mM
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Incubation Time:6 days
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Result:Induced dose-dependent reduction in cell viability in NCI-H358 cells with an IC50 of 199 nM.
Induced dose-dependent reduction in cell viability in SW 837 cells with an IC50 of 367 nM.
Induced dose-dependent reduction in cell viability in SW 1463 cells with an IC50 of 14 nM.
Induced dose-dependent reduction in cell viability in NCI-H1975 cells with an IC50 of 261 nM.
Induced dose-dependent reduction in cell viability in NCI-HCC827 cells with an IC50 of 101 nM.
Induced dose-dependent reduction in cell viability in NCI-N87 cells with an IC50 of 25 nM.
Parmacokinetics
| Species | Dose | Route | T1/2 | AUC | CLplasma | Vdss | Tmax | Cmax | Bioavailability |
|---|---|---|---|---|---|---|---|---|---|
| Mice[1] | 1 mg/kg | i.v. | 4.2 h | 36.2 μM·h | 1.0 mL/min/kg | 0.3 L/kg | / | / | / |
| Mice[1] | 3 mg/kg | p.o. | / | 43.0 μM·h | / | / | 1 h | 5.4 μM | 40 % |
| Rat[1] | 0.45 mg/kg | i.v. | 3.7 h | 6.5 μM·h | 2.4 mL/min/kg | 0.7 L/kg | / | / | / |
| Rat[1] | 0.9 mg/kg | p.o. | / | 9.4 μM·h | / | / | 1.5 h | 2.1 μM | 78 % |
| Dog[1] | 0.1 mg/kg | i.v. | 13.8 h | 0.8 μM·h | 5.1 mL/min/kg | 2.6 L/kg | / | / | / |
| Dog[1] | 0.25 mg/kg | p.o. | / | 0.9 μM·h | / | / | 3 h | 0.06 μM | 49 % |
In Vivo
I-0436650 (20 mg/kg; p.o.; once daily; 21 days), when combined with Osimertinib (HY-15772), restores antitumor efficacy in osimertinib-resistant NCI-H1975 xenografts, achieving 65% tumor growth inhibition relative to vehicle[1].
I-0436650 (20 mg/kg; p.o.; once daily) potentiates the antitumor activity of adagrasib in KRASG12C-mutant NCI-H2122 xenografts, achieving 86% tumor growth inhibition relative to vehicle on day 21 and delaying tumor relapse[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:CD1 nude mice (female)[1]
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Dosage:20 mg/kg; 40 mg/kg; 80 mg/kg
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Administration:p.o.; once daily; 21 days; p.o.; twice daily; 21 days
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Result:Reduced tumor volumes to 42.6% of vehicle controls with 20 mg/kg QD dose on day 21.
Reduced tumor volumes to 18.6% of vehicle controls with 20 mg/kg BID dose on day 21.
Reduced tumor volumes to 29.1% of vehicle controls with 40 mg/kg QD dose on day 21.
Reduced tumor volumes to 11.7% of vehicle controls with 80 mg/kg QD dose on day 21.
Achieved 88.3% tumor growth inhibition with 80 mg/kg once daily relative to vehicle.
Reduced pERK-positive tumor cell density relative to vehicle controls.
Reduced Ki67-positive proliferating cell density relative to vehicle controls.
Caused no significant body weight changes with all dosing regimens.
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Animal Model:CD1 nude mice (female)[1]
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Dosage:20 mg/kg
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Administration:p.o.; once daily; 21 days
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Result:Reduced tumor volumes to 35% of vehicle controls when combined with osimertinib 5 mg/kg QD on day 21.
Achieved 65% tumor growth inhibition relative to vehicle when combined with osimertinib.
Restored antitumor activity in osimertinib-resistant model.
Caused no increased toxicity relative to single agents.
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Animal Model:CD1 nude mice[1]
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Dosage:20 mg/kg
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Administration:p.o.; once daily
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Result:Reduced tumor volumes to 52% of vehicle controls with monotherapy on day 21.
Reduced tumor volumes to 14% of vehicle controls when combined with adagrasib 50 mg/kg QD on day 21.
Achieved 86% tumor growth inhibition relative to vehicle on day 21 when combined with adagrasib.
Enhanced initial tumor growth inhibition compared to adagrasib monotherapy.
Delayed tumor relapse compared to adagrasib monotherapy when monitored up to 40 days.
Chemical Information
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CAS No. 2843690-50-4
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Masse moléculaire 479.99
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Formule C22H22ClN9S
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SMILES
ClC1=C(N2C=CC=N2)N=CC=C1SC3=NC=C(N4CCC5(CC4)[C@@H](C6=CC=NN6C5)N)N=C3
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
Références
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
I-0436650 Related Classifications
HY-189075 Related Classifications
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