Art. -Nr.: HY-189075

I-0436650

I-0436650 is an orally active SHP2 inhibitor with an IC₅₀ of 4 nM and a K_d 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. Nr.: 2843690-50-4
Formel: C₂₂H₂₂ClN₉S
Molecular Weight:479.99

Speicherung:

Please store the product under the recommended conditions in the Certificate of Analysis.

I-0436650 Chemical Structure

CAS. Nr.: 2843690-50-4

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Biologische Aktivität
- Beschreibung
- IC₅₀ & Target
- Cellular Effect
- In Vitro
- Parmacokinetics
- In Vivo
Chemical Information
Reinheit & Dokumentation
Verweise
Calculators
Help & FAQs
Classifications
Bioz

Biologische Aktivität

Beschreibung

IC₅₀ & Target

^[1]

SHP2

4 nM (IC₅₀)

SHP2

0.3 nM (Kd)

ERK

p38 MAPK

EGFR

Ras

RTK

Alle ERK Isoform-spezifische Produkte anzeigen :

Alle p38 MAPK Isoform-spezifische Produkte anzeigen :

Alle EGFR Isoform-spezifische Produkte anzeigen :

Alle Ras Isoform-spezifische Produkte anzeigen :

Cellular Effect

Cell Line	Type	Value	Description	References
KYSE-520 cell line	IC50	13 nM	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.	42593923
KYSE-520 cell line	IC50	216 nM	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.	42593923
NCI-H358	IC50	199 nM	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.	42593923
SW837	IC50	367 nM	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.	42593923
SW1463	IC50	14 nM	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.	42593923
NCI-H1975	IC50	261 nM	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.	42593923
HCC827	IC50	101 nM	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.	42593923
NCI-N87	IC50	25 nM	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.	42593923
NCI-H358	IC50	61 nM	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	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	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.

Cell Proliferation Assay^[1]

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
Concentration:

1 pM-10 mM
Incubation Time:

6 days
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	T_1/2	AUC	CL_plasma	V_dss	T_max	C_max	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 (20-80 mg/kg; p.o.; once/twice daily; 21 days) exhibits dose-dependent antitumor activity in NCI-H1975 xenografts, achieving the greatest efficacy at 80 mg/kg once daily with 88.3% tumor growth inhibition relative to vehicle, while maintaining good tolerability^[1].
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 KRAS^G12C-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.

Animal Model:

CD1 nude mice (female)^[1]
Dosage:

20 mg/kg; 40 mg/kg; 80 mg/kg
Administration:

p.o.; once daily; 21 days; p.o.; twice daily; 21 days
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.

Animal Model:

CD1 nude mice (female)^[1]
Dosage:

20 mg/kg
Administration:

p.o.; once daily; 21 days
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.

Animal Model:

CD1 nude mice^[1]
Dosage:

20 mg/kg
Administration:

p.o.; once daily
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

CAS. Nr. 2843690-50-4
Molecular Weight 479.99
Formel C₂₂H₂₂ClN₉S
SMILES

ClC1=C(N2C=CC=N2)N=CC=C1SC3=NC=C(N4CCC5(CC4)[C@@H](C6=CC=NN6C5)N)N=C3
Versand

Room temperature in continental US; may vary elsewhere.
Speicherung

Please store the product under the recommended conditions in the Certificate of Analysis.

Reinheit & Dokumentation

Handling Instructions (2659 KB)

Verweise

[1]. Ciammaichella A, et al. Discovery and Preclinical Characterization of I-0436650, a Selective SHP2 Allosteric Inhibitor for RAS-Driven Cancers. Journal of medicinal chemistry. 2026 Aug 13;69(15):18898-18914.

Calculators

Molaritätsrechner

Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

Mass Mass

Konzentration Konzentration

Volumen Volumen

Molecular Weight Molecular Weight

Verdünnungsrechner

Konzentration _{(Stammlösung)} × Volumen _{(Stammlösung)} = Konzentration _{(Ziellösung)} × Volumen _{(Ziellösung)}

Konzentration _{(Stammlösung)} Konzentration _{(Stammlösung)}

Volumen _{(Stammlösung)} Volumen _{(Stammlösung)}

Konzentration _{(Ziellösung)} Konzentration _{(Ziellösung)}

Volumen _{(Ziellösung)} Volumen _{(Ziellösung)}

Help & FAQs

How should lyophilized recombinant proteins be reconstituted and stored?

1. Before opening the cap, centrifuge the vial at 13000 rpm for 20-30 seconds. This step will ensure that any lyophilized powder that may have adhered to the cap or walls is collected at the bottom of the vial, minimizing the risk of product loss.

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I-0436650

Alle ERK Isoform-spezifische Produkte anzeigen

Alle p38 MAPK Isoform-spezifische Produkte anzeigen

Alle EGFR Isoform-spezifische Produkte anzeigen

Alle Ras Isoform-spezifische Produkte anzeigen