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AZD-9291

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AZD-9291 is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that binds to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion) that predominate in non-small cell lung cancer (NSCLC) tumours following treatment with first-line EGFR-TKIs.

Product Description

Basic Characteristics

Product Name AZD-9291
CAS Number 1421373-65-0
Molecular Formula C28H33N7O2
Formula Weight 499.6
Synonyms 1421373-65-0;

osimertinib;

Mereletinib;

AZD9291;

N-[2-[[2-(dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide.

Appearance White to off-white crystalline powder
Storage and Handling Store at room temperature between 20°C-25°C

 

AZD-9291 Description

AZD-9291 is a targeted therapy that targets the mutated epidermal growth factor receptor (EGFR) T790M within the cancer cell.

The EGFR gene plays an important role in both normal and cancer cells. This gene leads to the production of EGFR protein. This protein is normally part of a chain of molecules that relay a signal that tells cells how to grow and divide. A change in the EGFR gene (called a mutation) can alter the way that the EGFR protein works. Instead of waiting for its turn to signal a cell to divide or grow, the EGFR protein is out of control and signals all of the time, this out of control EGFR signaling may drive the uncontrolled growth of cancer cells. AZD-9291 targets select mutant forms of EGFR, including t790M, L858R and exon 19-deletion. AZD-9291 is selective for sensitizing mutations and the T790M resistance mutation, which is the most common mechanism of resistance to EGFR tyrosine kinase inhibitors.

 

AZD-9291 Mechanism of Action

AZD-9291 is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that binds to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion) that predominate in non-small cell lung cancer (NSCLC) tumours following treatment with first-line EGFR-TKIs. As a third-generation tyrosine kinase inhibitor, AZD-9291 is specific for the gate-keeper T790M mutation which increases ATP binding activity to EGFR and results in poor prognosis for late-stage disease. Furthermore, AZD-9291(osimertinib) has been shown to spare wild-type EGFR during therapy, thereby reducing non-specific binding and limiting toxicity.

 

AZD-9291 Application

AZD9291 is a prescription medicine for non-small cell lung cancer (NSCLC) that has spread to other parts of the body (metastatic). AZD9291 is used:

▪ As your first treatment if tumors have a certain abnormal epidermal growth factor receptor (EGFR) gene(s).

▪ If you have a certain type of EGFR gene and were previously treated with an EGFR tyrosine kinase inhibitor (TKI) medicine that did not work or is no longer working.

 

AZD-9291 Side Effects & Warning

AZD-9291 may cause serious side effects, including:

▲ lung problems. AZD-9291 may cause lung problems that may lead to death. Symptoms may be similar to symptoms from lung cancer. Tell your doctor right away if you have any new or worsening lung symptoms, including trouble breathing, shortness of breath, cough, or fever

▲ heart problems, including heart failure. AZD-9291 may cause heart problems that may lead to death. Your doctor should check your heart function before you start taking AZD-9291 and during treatment as needed. Tell your doctor right away if you have any of the following signs and symptoms of a heart problem: feeling like your heart is pounding or racing, shortness of breath, swelling of your ankles and feet, feeling lightheaded

▲ eye problems. AZD-9291 may cause eye problems. Tell your doctor right away if you have symptoms of eye problems which may include watery eyes, sensitivity to light, eye pain, eye redness, or vision changes. Your doctor may send you to see an eye specialist (ophthalmologist) if you get eye problems with AZD-9291.

▲ skin problems. AZD-9291 may cause skin problems. Tell your doctor right away if you develop target lesions (skin reactions that look like rings), severe blistering or peeling of the skin

 

The most common side effects of AZD-9291 are:

▪ diarrhea

▪ rash

▪ dry skin

▪ changes in your nails, including: redness, tenderness, pain, inflammation, brittleness, separation from nailbed, and shedding of nails

▪ mouth sores

▪ tiredness

▪ decreased appetite

These are not all the possible side effects of AZD-9291. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

 

Reference

[1] Cross DA, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014 Sep;4(9):1046-61.

[2] Finlay MR, et al. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistancemutations that spares the wild type form of the receptor. J Med Chem. 2014 Oct 23;57(20):8249-67.

[3] Hu X, Zhang ZY, et al. “A natural anthraquinone derivative shikonin synergizes with AZD9291 against wtEGFR NSCLC cells through reactive oxygen species-mediated endoplasmic reticulum stress.” Phytomedicine. 2020;68:153189. PMID:32070867

[4] Richtmann S, Wilkens D, et al. “FAM83A and FAM83B as Prognostic Biomarkers and Potential New Therapeutic Targets in NSCLC.” Cancers (Basel). 2019 May 11;11(5). pii: E652. PMID:31083571

[5] Cheriyan VT, Alsaab H, et al. “A CARP-1 functional mimetic compound is synergistic with BRAF-targeting in non-small cell lung cancers.” Oncotarget. 2018 Jul 3;9(51):29680-29697. PMID:30038713

[6] Darren Cross1, Sue Ashton1, Caroline Nebhan2 et al. AZD9291: an irreversible, potent and selective third generation tyrosine kinase inhibitor (TKI) targeting EGFR activating (EGFRm+) and resistance (T790M) mutations in advanced lung adenocarcinoma. Mol Cancer Ther 2013;12(11 Suppl):A109.

[7] Liu YN, .et al. Acquired resistance to EGFR tyrosine kinase inhibitors is mediated by the reactivation of STC2/JUN/AXL signaling in lung cancer, Int J Cancer, 2019, Jun 4 PMID: 31162839