Osimertinib free base
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MedKoo CAT#: 206042

CAS#: 1421373-65-0 (free base)

Description: Osimertinib, also known as AZD-9291 and Mereletinib, is a third-generation EGFR inhibitor, showed promise in preclinical studies and provides hope for patients with advanced lung cancers that have become resistant to existing EGFR inhibitors. AZD9291 is highly active in preclinical models and is well tolerated in animal models. It inhibits both activating and resistant EGFR mutations while sparing the normal form of EGFR that is present in normal skin and gut cells, thereby reducing the side effects encountered with currently available medicines. Osimertinib was approved in Nov. 2015 by FDA.


Chemical Structure

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Osimertinib free base
CAS# 1421373-65-0 (free base)

Theoretical Analysis

MedKoo Cat#: 206042
Name: Osimertinib free base
CAS#: 1421373-65-0 (free base)
Chemical Formula: C28H33N7O2
Exact Mass: 499.26957
Molecular Weight: 499.61
Elemental Analysis: C, 67.31; H, 6.66; N, 19.62; O, 6.40

Price and Availability

Size Price Availability Quantity
500.0mg USD 90.0 Ready to ship
1.0g USD 150.0 Ready to ship
2.0g USD 250.0 Ready to ship
5.0g USD 550.0 Ready to ship
10.0g USD 950.0 Ready to ship
20.0g USD 1650.0 Ready to ship
50.0g USD 3650.0 Ready to ship
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Related CAS #: 1421373-65-0 (free base)   1421373-66-1 (mesylate)    

Synonym: AZD9291; AZD 9291; AZD-9291; AZD-9291 freebase; Mereletinib; Osimertinib free base; trade name Tagrisso.

IUPAC/Chemical Name: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

InChi Key: DUYJMQONPNNFPI-UHFFFAOYSA-N

InChi Code: InChI=1S/C28H33N7O2/c1-7-27(36)30-22-16-23(26(37-6)17-25(22)34(4)15-14-33(2)3)32-28-29-13-12-21(31-28)20-18-35(5)24-11-9-8-10-19(20)24/h7-13,16-18H,1,14-15H2,2-6H3,(H,30,36)(H,29,31,32)

SMILES Code: C=CC(NC1=CC(NC2=NC=CC(C3=CN(C)C4=C3C=CC=C4)=N2)=C(OC)C=C1N(CCN(C)C)C)=O

Appearance: Brown to yellow solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Osimertinib (AZD-9291) is an irreversible and mutant selective EGFR inhibitor with IC50s of 12 and 1 nM against EGFRL858R and EGFRL858R/T790M, respectively.
In vitro activity: EGFR T790M mutant NCI-H1975 cells were treated with different concentrations of osimertinib. After treatment for 24 h, osimertinib clearly inhibited EGFR phosphorylation and significantly reduced the protein levels of PD-L1 (Figure 1A). NCI-H1975 cells were then incubated with 125 nmol/L osimertinib for different durations (3, 6, 12 and 24 h). As shown in Figure 1B, osimertinib down-regulated PD-L1 expression at 6 h. Furthermore, immunofluorescence was used to localize PD-L1 in NCI-H1975 cells. Compared with the osimertinib-untreated group, cell membranes exhibited weak PD-L1 signals at 6 and 24 h (Figure 1C). Consistently, the reduction of PD-L1 on the membranes was confirmed further by flow cytometry after treatment with osimertinib for 6 and 24 h (Figure 1D). To exclude the massive suppression of PD-L1 mRNA and protein expression caused by cell death, this study performed MTT assays to examine the cell viability after treatment with osimertinib. This study found that osimertinib could not trigger cell death in NCI-H1975 cells at 6 h (Figure 1E), which was further verified in HCC827 cells (data not shown). In addition, the apoptosis inhibitor Z-VAD-FMK and the necroptosis inhibitor NSA failed to reverse the osimertinib-triggered decrease of PD-L1 in NCI-H1975 cells (Figure 1F). Collectively, these findings demonstrate that osimertinib reduces PD-L1 expression in NCI-H1975 cells independent of cell death. Reference: Acta Pharmacol Sin. 2017 Nov; 38(11): 1512–1520. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5672073/
In vivo activity: To explore the influence of CYP1A enzymes on osimertinib disposition in vivo, this study carried out pharmacokinetic analysis in novel Cyp1a1/1a2 knockout and CYP1A1/1A2 humanized mouse lines. The basal expression of CYP1A1 in the h1A1/1A2 line is low, however it can be induced in a number of tissues including liver, lung, and small intestine by exposure of the mice to TCDD, an activator of the Ah receptor (Ahr). In h1A1/1A2 mice pretreated with TCDD, there was a 3.4-fold decrease in AUC0−t and a 3.3-fold decrease in Cmax of osimertinib (Fig. 5A and Supplementary Table S7). There was no change in exposure in the 1a1/1a2KO line. Correspondingly, TCDD-pretreatment greatly increased circulating levels of the OH-1 metabolite in humanized mice, but had no effect in knockouts (Fig. 5B). In this experiment, TCDD-mediated activation of Ahr occurred in several tissues—liver, small intestine, and lung—hence the effects on osimertinib and metabolite disposition were likely to be driven by a combination of hepatic, intestinal, and pulmonary CYP1A1/1A2. Reference: Clin Cancer Res. 2018 May 1;24(9):2138-2147. https://clincancerres.aacrjournals.org/content/24/9/2138.long

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 15.0 30.0

Preparing Stock Solutions

The following data is based on the product molecular weight 499.61 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Chagoya G, Kwatra SG, Nanni CW, Roberts CM, Phillips SM, Nullmeyergh S, Gilmore SP, Spasojevic I, Corcoran DL, Young CC, Ballman KV, Ramakrishna R, Cross DA, Markert JM, Lim M, Gilbert MR, Lesser GJ, Kwatra MM. Efficacy of osimertinib against EGFRvIII+ glioblastoma. Oncotarget. 2020 Jun 2;11(22):2074-2082. doi: 10.18632/oncotarget.27599. PMID: 32547705; PMCID: PMC7275784. 2. Jiang XM, Xu YL, Huang MY, Zhang LL, Su MX, Chen X, Lu JJ. Osimertinib (AZD9291) decreases programmed death ligand-1 in EGFR-mutated non-small cell lung cancer cells. Acta Pharmacol Sin. 2017 Nov;38(11):1512-1520. doi: 10.1038/aps.2017.123. Epub 2017 Sep 7. PMID: 28880013; PMCID: PMC5672073. 3. MacLeod AK, Lin D, Huang JT, McLaughlin LA, Henderson CJ, Wolf CR. Identification of Novel Pathways of Osimertinib Disposition and Potential Implications for the Outcome of Lung Cancer Therapy. Clin Cancer Res. 2018 May 1;24(9):2138-2147. doi: 10.1158/1078-0432.CCR-17-3555. Epub 2018 Feb 6. PMID: 29437786. 4. Floc'h N, Martin MJ, Riess JW, Orme JP, Staniszewska AD, Ménard L, Cuomo ME, O'Neill DJ, Ward RA, Finlay MRV, McKerrecher D, Cheng M, Vang DP, Burich RA, Keck JG, Gandara DR, Mack PC, Cross DAE. Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions. Mol Cancer Ther. 2018 May;17(5):885-896. doi: 10.1158/1535-7163.MCT-17-0758. Epub 2018 Feb 26. PMID: 29483211; PMCID: PMC5932243.
In vitro protocol: 1. Chagoya G, Kwatra SG, Nanni CW, Roberts CM, Phillips SM, Nullmeyergh S, Gilmore SP, Spasojevic I, Corcoran DL, Young CC, Ballman KV, Ramakrishna R, Cross DA, Markert JM, Lim M, Gilbert MR, Lesser GJ, Kwatra MM. Efficacy of osimertinib against EGFRvIII+ glioblastoma. Oncotarget. 2020 Jun 2;11(22):2074-2082. doi: 10.18632/oncotarget.27599. PMID: 32547705; PMCID: PMC7275784. 2. Jiang XM, Xu YL, Huang MY, Zhang LL, Su MX, Chen X, Lu JJ. Osimertinib (AZD9291) decreases programmed death ligand-1 in EGFR-mutated non-small cell lung cancer cells. Acta Pharmacol Sin. 2017 Nov;38(11):1512-1520. doi: 10.1038/aps.2017.123. Epub 2017 Sep 7. PMID: 28880013; PMCID: PMC5672073.
In vivo protocol: 1. MacLeod AK, Lin D, Huang JT, McLaughlin LA, Henderson CJ, Wolf CR. Identification of Novel Pathways of Osimertinib Disposition and Potential Implications for the Outcome of Lung Cancer Therapy. Clin Cancer Res. 2018 May 1;24(9):2138-2147. doi: 10.1158/1078-0432.CCR-17-3555. Epub 2018 Feb 6. PMID: 29437786. 2. Floc'h N, Martin MJ, Riess JW, Orme JP, Staniszewska AD, Ménard L, Cuomo ME, O'Neill DJ, Ward RA, Finlay MRV, McKerrecher D, Cheng M, Vang DP, Burich RA, Keck JG, Gandara DR, Mack PC, Cross DAE. Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions. Mol Cancer Ther. 2018 May;17(5):885-896. doi: 10.1158/1535-7163.MCT-17-0758. Epub 2018 Feb 26. PMID: 29483211; PMCID: PMC5932243.

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Additional Information

Related CAS#
CAS#1421373-65-0 (Osimertinib free base);
CAS#1421373-66-1 (Osimertinib mesylate salt)