1. Protein Tyrosine Kinase/RTK
  2. ALK
    Insulin Receptor
    IGF-1R

LDK378 (Synonyms: Ceritinib)

Cat. No.: HY-15656 Purity: 99.75%
Data Sheet SDS Handling Instructions

LDK378 is a potent and more specific ALK inhibitor with IC50 of 0.2 nM.

For research use only. We do not sell to patients.
LDK378 Chemical Structure

LDK378 Chemical Structure

CAS No. : 1032900-25-6

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Other Forms of LDK378:

  • Biological Activity

  • Protocol

  • Technical Information

  • Purity & Documentation

  • References

Description

LDK378 is a potent and more specific ALK inhibitor with IC50 of 0.2 nM.

IC50 & Target

IC50: 0.2 nM (ALK), 7 nM (InsR), 8 nM (IGF-1R), 23 nM (STK22D), 60 nM (FLT3), 260 nM (FGFR2)[1]

In Vitro

LDK378 (Ceritinib) also inhibits RET (IC50=400 nM), FGFR3 (IC50=430 nM), LCK (IC50=560 nM), JAK2 (IC50=610 nM), Aurora (IC50=660 nM), LYN (50=840 nM), EGFR (IC50=900 nM), and FGFR4 (IC50=950 nM)[1]. LDK378 retains high potency against the ALK enzymatic activity with an IC50 value of 200 pM and shows only strong inhibition against IGF-1R, InsR, and STK22D out of a panel of 46 kinases with a minimum selectivity of 70-fold. In Ba/F3 cells transfected with various kinases, LDK378 inhibits ALK activity with an IC50 value of 40.7 nM and had IC50 values of >100 nM against all other kinases tested. LDK378 shows potent antiproliferative activity with an IC50 value of 22.8 nM in Karpas 299 human non-Hodgkin’s Ki-positive large cell lymphoma carrying the NPM-ALK fusion gene and 26 nM in Ba/F3 cells transfected with the NPM-ALK fusion gene. LDK378 also shows good selectivity over wild-type Ba/F3 cells (IC50>2 μM) and Ba/F3 cells transfected with Tel-InsR gene (IC50=320 nM)[2].

In Vivo

The t1/2 of LDK378 in LDK378 mouse rat, dog, and monkey is 6.2 h, 9.1 h, 21 h, and 26 h,respectively[1]. LDK378 has an excellent pharmacokinetics profile in rodents and non-rodents with an oral bioavailability of >50%. LDK378 demonstrates dose-dependent tumor growth inhibition and achieved partial tumor regression in the Karpas 299 rat xenograft model with daily administration but is capable of achieving complete tumor regression in the H2228 NSCLC rat xenograft model, which carries the EML4-ALK fusion gene. In both models, LDK378 is well tolerated in animals. LDK378 is further assessed for its ADME profile and is found to have a relatively good metabolic stability in liver microsomes, modest CYP3A4 inhibition, some hERG inhibition with an IC50 value of 46 μM in hERG patch clamp experiments, but no evidence of QTc prolongation in both dog and monkey telemetry studies[2].

Clinical Trial
NCT Number Sponsor Condition Start Date Phase
NCT02638909 Criterium, Inc.|University of Colorado, Denver|Novartis Colorectal Adenocarcinoma|Cholangiocarcinoma|Pancreatic Adenocarcinoma|Hepatocellular Adenocarcinoma|Gastric Adenocarcinoma|Esophageal Adenocarcinoma December 2015 Phase 2
NCT03087448 University of California, San Francisco|Novartis Pharmaceuticals|University of California, Davis|University of California, Los Angeles|University of California, San Diego|University of California, Irvine Non-small Cell Lung Cancer June 2017 Phase 1|Phase 2
NCT02343679 Anne Beaven, MD|Novartis|Duke University Hematologic Malignancies May 2015 Phase 2
NCT02186821 Novartis Pharmaceuticals|Novartis Tumors With Aberrations in ALK or ROS1 September 2014 Phase 2
NCT02321501 M.D. Anderson Cancer Center|Novartis Head and Neck Cancer|Lung Cancer June 2016 Phase 1
NCT02299505 Novartis Pharmaceuticals|Novartis Non-Small Cell Lung Cancer April 9, 2015 Phase 1
NCT02584933 Novartis Pharmaceuticals|Novartis ALK Positive Malignancies December 2015 Phase 4
NCT02292550 Novartis Pharmaceuticals|Novartis Non-small Cell Lung Cancer May 14, 2015 Phase 1|Phase 2
NCT02465528 Novartis Pharmaceuticals|Novartis Tumors With Aberrations in ALK May 6, 2016 Phase 2
NCT02289144 University of Texas Southwestern Medical Center|Novartis Metastatic Anaplastic Thyroid Cancer|Locally Advanced Anaplastic, Undifferentiated Thyroid Cancer June 2015 Phase 2
NCT02729961 University of Washington|National Cancer Institute (NCI) Anaplastic Large Cell Lymphoma, ALK-Positive|Systemic Anaplastic Large Cell Lymphoma August 1, 2017 Phase 1|Phase 2
NCT02513667 University of Texas Southwestern Medical Center|Novartis Pharmaceuticals ALK-positive Non-small Cell Lung Cancer November 2015 Phase 2
NCT02422589 Novartis Pharmaceuticals|Novartis ALK-positive Advanced Tumors October 23, 2015 Phase 1
NCT02227940 Roswell Park Cancer Institute|National Cancer Institute (NCI) Advanced Malignant Solid Neoplasm|ALK Positive|Metastatic Pancreatic Adenocarcinoma|Stage III Pancreatic Cancer|Stage IV Pancreatic Cancer January 8, 2015 Phase 1
NCT02605746 St. Joseph's Hospital and Medical Center, Phoenix|Novartis|Wayne State University|Translational Genomics Research Institute Glioblastoma|Brain Metastases November 2015 Early Phase 1
NCT02393625 Novartis Pharmaceuticals|Novartis ALK-positive NSCLC May 27, 2015 Phase 1
NCT02780128 Yael P Mosse|Novartis Pharmaceuticals|Foundation Medicine|Children's Hospital of Philadelphia Neuroblastoma|Cancer July 2016 Phase 1
NCT02587650 Adil Daud|University of California, San Francisco Melanoma May 2016 Phase 2
NCT02638909 Criterium, Inc.|University of Colorado, Denver|Novartis Colorectal Adenocarcinoma|Cholangiocarcinoma|Pancreatic Adenocarcinoma|Hepatocellular Adenocarcinoma|Gastric Adenocarcinoma|Esophageal Adenocarcinoma December 2015 Phase 2
NCT03087448 University of California, San Francisco|Novartis Pharmaceuticals|University of California, Davis|University of California, Los Angeles|University of California, San Diego|University of California, Irvine Non-small Cell Lung Cancer June 2017 Phase 1|Phase 2
NCT02343679 Anne Beaven, MD|Novartis|Duke University Hematologic Malignancies May 2015 Phase 2
NCT02186821 Novartis Pharmaceuticals|Novartis Tumors With Aberrations in ALK or ROS1 September 2014 Phase 2
NCT02321501 M.D. Anderson Cancer Center|Novartis Head and Neck Cancer|Lung Cancer June 2016 Phase 1
NCT02299505 Novartis Pharmaceuticals|Novartis Non-Small Cell Lung Cancer April 9, 2015 Phase 1
NCT02584933 Novartis Pharmaceuticals|Novartis ALK Positive Malignancies December 2015 Phase 4
NCT02292550 Novartis Pharmaceuticals|Novartis Non-small Cell Lung Cancer May 14, 2015 Phase 1|Phase 2
NCT02465528 Novartis Pharmaceuticals|Novartis Tumors With Aberrations in ALK May 6, 2016 Phase 2
NCT02289144 University of Texas Southwestern Medical Center|Novartis Metastatic Anaplastic Thyroid Cancer|Locally Advanced Anaplastic, Undifferentiated Thyroid Cancer June 2015 Phase 2
NCT02729961 University of Washington|National Cancer Institute (NCI) Anaplastic Large Cell Lymphoma, ALK-Positive|Systemic Anaplastic Large Cell Lymphoma August 1, 2017 Phase 1|Phase 2
NCT02513667 University of Texas Southwestern Medical Center|Novartis Pharmaceuticals ALK-positive Non-small Cell Lung Cancer November 2015 Phase 2
NCT02422589 Novartis Pharmaceuticals|Novartis ALK-positive Advanced Tumors October 23, 2015 Phase 1
NCT02227940 Roswell Park Cancer Institute|National Cancer Institute (NCI) Advanced Malignant Solid Neoplasm|ALK Positive|Metastatic Pancreatic Adenocarcinoma|Stage III Pancreatic Cancer|Stage IV Pancreatic Cancer January 8, 2015 Phase 1
NCT02605746 St. Joseph's Hospital and Medical Center, Phoenix|Novartis|Wayne State University|Translational Genomics Research Institute Glioblastoma|Brain Metastases November 2015 Early Phase 1
NCT02393625 Novartis Pharmaceuticals|Novartis ALK-positive NSCLC May 27, 2015 Phase 1
NCT02780128 Yael P Mosse|Novartis Pharmaceuticals|Foundation Medicine|Children's Hospital of Philadelphia Neuroblastoma|Cancer July 2016 Phase 1
NCT02587650 Adil Daud|University of California, San Francisco Melanoma May 2016 Phase 2
NCT02450903 Novartis Pharmaceuticals|Novartis Non-Small-Cell Lung Cancer August 21, 2015 Phase 2
NCT01685138 Novartis Pharmaceuticals|Novartis Non-Small Cell Lung Cancer December 20, 2012 Phase 2
NCT01685060 Novartis Pharmaceuticals|Novartis Non-Small Cell Lung Cancer November 26, 2012 Phase 2
NCT02040870 Novartis Pharmaceuticals|Novartis Non-Small Cell Lung Cancer March 7, 2014 Phase 1|Phase 2
NCT01634763 Novartis Pharmaceuticals|Novartis Tumors Characterized by Genetic Alterations in Anaplastic Lymphoma Kinase (ALK) June 2012 Phase 1
NCT01742286 Novartis Pharmaceuticals|Novartis Anaplastic Lymphoma Kinase August 28, 2013 Phase 1
NCT01950481 Novartis Pharmaceuticals|Novartis Normal Hepatic Function|Impaired Hepatic Function January 2014 Phase 1
NCT01283516 Novartis Pharmaceuticals|Novartis Tumors Characterized by Genetic Abnormalities of ALK January 2011 Phase 1
NCT02374489 National Health Research Institutes, Taiwan|National Cheng-Kung University Hospital|National Taiwan University Hospital Cholangiocarcinoma March 2015 Phase 2
NCT01828099 Novartis Pharmaceuticals|Novartis Non-Small Cell Lung Cancer July 2013 Phase 3
NCT01772797 Novartis Pharmaceuticals|Novartis Anaplastic Lymphoma Kinase (ALK)|Non-small Cell Lung Cancer June 2013 Phase 1
NCT01828112 Novartis Pharmaceuticals|Novartis Non-Small Cell Lung Cancer June 2013 Phase 3
NCT01947608 Novartis Pharmaceuticals|Novartis Non-small Cell Lung Cancer (NSCLC)
NCT01964157 Yonsei University Non-small Cell Lung Cancer (NSCLC) September 1, 2013 Phase 2
NCT02276027 Novartis Pharmaceuticals|Novartis Adenocarcinoma Lung Cancer; Squamous Cell Lung Carcinoma January 20, 2015 Phase 2
NCT02336451 Novartis Pharmaceuticals|Novartis ALK-positive Non-small Cell Lung Cancer April 1, 2015 Phase 2
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References
Preparing Stock Solutions
Concentration Volume (DMSO) Mass 1 mg 5 mg 10 mg
1 mM 1.7917 mL 8.9583 mL 17.9167 mL
5 mM 0.3583 mL 1.7917 mL 3.5833 mL
10 mM 0.1792 mL 0.8958 mL 1.7917 mL
Animal Administration
[1]

LDK378 (HCl salt) is formulated as a solution in 75% PEG300/25% D5W[1].
LDK378 (phosphate salt) as an intravenous solution in 30% propylene glycol/5% solutol buffer and an oral suspension in suspension in 0.5% (w/v) aqueous methylcellulose/0.5% Tween 80[1].
LDK378 (free base) as an intravenous solution in 30% propylene glycol/5% solutol and an oral suspension in 0.5% (w/v) methylcellulose[1].

In vivo PK studies are conducted in mice, rats, dogs, and cynomolgus monkeys. LDK378 (HCl salt) is administered to male Balb/c mice intravenously via tail vein at 5 mg/kg (n=3) and orally via gavage at 20 mg/kg (n=3). By use of the same formulation, LDK378 (HCl salt) is dosed to Sprague-Dawley rats intravenously via the tail vein at 3 mg/kg (n=3) and orally via gavage at 10 mg/kg (n=3). Blood samples are collected serially at scheduled times over 24 h after dosing. Male beagle dogs receive a single intravenous (n=2) or oral (n=3) dose of LDK378 (phosphate salt) as an intravenous solution at 5 mg/kg and an oral suspension at 20 mg/kg, respectively. Male cynomologus monkeys receive single intravenous (n=2) or oral (n=3) dose of LDK378 (free base) as an intravenous solution at 5 mg/kg and an oral suspension at 60 mg/kg, respectively. Blood samples for plasma are collected at prescheduled times over 144 h after dosing[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References
Molecular Weight

558.14

Formula

C₂₈H₃₆ClN₅O₃S

CAS No.

1032900-25-6

Storage

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

Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

DMSO: 5.6 mg/mL (Need ultrasonic)

LDK378 (Ceritinib) is dissolved in 0.5% methylcellulose, 0.5% Tween 80 with sterile water[3].

* "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

References

Purity: 99.75%

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LDK378
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