Abivertinib
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MedKoo CAT#: 563435

CAS#: 1557267-42-1 (free base)

Description: Abivertinib, also known as AC0010 and Avitinib, is a third-generation EGFR tyrosine kinase inhibitor and BTK Inhibitor that demonstrated clinical efficacy and manageable adverse events (AEs). Abivertinib inhibits cell proliferation, reduces colony-forming capacity, and induces apoptosis and cell cycle arrest in AML cells, especially those harboring FLT3-ITD mutations. Abivertinib was also found to be more sensitive than ibrutinib in treating AML. Abivertinib may be a promising novel agent for AML, with potential for combination treatment with HHT.


Chemical Structure

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Abivertinib
CAS# 1557267-42-1 (free base)

Theoretical Analysis

MedKoo Cat#: 563435
Name: Abivertinib
CAS#: 1557267-42-1 (free base)
Chemical Formula: C26H26FN7O2
Exact Mass: 487.2132
Molecular Weight: 487.53
Elemental Analysis: C, 64.05; H, 5.38; F, 3.90; N, 20.11; O, 6.56

Price and Availability

Size Price Availability Quantity
25.0mg USD 150.0 Ready to ship
50.0mg USD 250.0 Ready to ship
100.0mg USD 450.0 Ready to ship
200.0mg USD 750.0 Ready to ship
500.0mg USD 1650.0 Ready to ship
1.0g USD 2950.0 2 Weeks
2.0g USD 5250.0 2 Weeks
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Related CAS #: 1557267-42-1 (free base)   1557268-88-8 (maleate)   1822357-78-7 (maleate hydrate)   1557268-90-2 (2HCl)   1801879-16-2 (HCl)    

Synonym: Abivertinib; AC0010; AC-0010; AC 0010; Avitinib;

IUPAC/Chemical Name: N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide

InChi Key: UOFYSRZSLXWIQB-UHFFFAOYSA-N

InChi Code: InChI=1S/C26H26FN7O2/c1-3-23(35)29-17-5-4-6-19(15-17)36-25-20-9-10-28-24(20)31-26(32-25)30-18-7-8-22(21(27)16-18)34-13-11-33(2)12-14-34/h3-10,15-16H,1,11-14H2,2H3,(H,29,35)(H2,28,30,31,32)

SMILES Code: C=CC(NC1=CC=CC(OC2=C3C(NC=C3)=NC(NC4=CC=C(N5CCN(C)CC5)C(F)=C4)=N2)=C1)=O

Appearance: 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

Shelf Life: >3 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: Abivertinib, also known as AC0010 and Avitinib, is a tyrosine kinase inhibitor and BTK Inhibitor.
In vitro activity: A proliferation assay with an appropriate concentration of Apigenin in combination with low-dose Abivertinib was examined in U2932 and OCI-LY10 for 48 hours. The results indicate that the cell viability of the combined group is significantly lower than either of the single drug groups (Fig. 3A, B). Next, the results of soft agar colony formation experiments further confirmed that the colony forming ability of the combined group in U2932 is sufficiently inhibited (Fig. 3D). In order to further explore the mechanism of the combination effect, apoptosis was detected in combination and single treatment groups. The results are shown in Fig. 3E and and 3F: the combination of two drugs at a lower concentration can significantly induce apoptosis and is more than any single drug group. In the search for apoptotic mechanisms, it was concluded that the combination of two drugs can down-regulate the anti-apoptotic proteins of BCL2 and BCL-XL (Fig. 4A), while the cleaved-PARP, cleaved-C3, cleaved-C8 were also captured (Fig. 4B). Meanwhile, the expression level of BCL-2 and BCL-XL of different treatment groups was studied by Westernblot assay of tumor tissue moved from DLBCL xenograft and turned out the similar result to cell lines (Fig. 4D). According to the results, it was concluded that Apigenin synergizes with Abivertinib to induce apoptosis in diffuse large B-cell lymphoma by down-regulating BCL2, BCL-XL and activating the caspase family. Reference: J Cancer. 2020 Feb 3;11(8):2123-2132. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32127939/
In vivo activity: All mice were treated as described in methods. Representative tumors in the xenograft mice treated in different groups are shown in Fig. 5A, the treatments of Apigenin and Abivertinib or their combination significantly reduced tumor mass compared to vehicle. In details, Apigenin, Abivertinib, COM decreased by 32.5%, 48%, 80% the tumor weight compared to vehicle group respectively (Fig. 5B).The similar results were found when refer to tumor size(Fig. 5C). Next, the tumor progression was analyzed by measuring the size of tumors in each group every 2 days, the result shown in Fig. 5D, the treatments effectively inhibit the growing of tumors. In order to measure the apoptosis induced by drugs, tunnel assay was played, the results showed increase in combination group (Fig. 5E and F). When the tumor burden on spleen and liver of mice was analyzed, the HE staining showed no significant difference among groups on liver while decreasing extramedullary hematopoiesis in combination group (Fig. 5G). All the results unveiled the fact that Apigenin can inhibit the DLBCL progression and can cooperate with Abivertinib to achieve better anti-lymphoma function. Reference: J Cancer. 2020 Feb 3;11(8):2123-2132. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32127939/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 30.0 61.53

Preparing Stock Solutions

The following data is based on the product molecular weight 487.53 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
In vitro protocol: 1. Huang S, Yu M, Shi N, Zhou Y, Li F, Li X, Huang X, Jin J. Apigenin and Abivertinib, a novel BTK inhibitor synergize to inhibit diffuse large B-cell lymphoma in vivo and vitro. J Cancer. 2020 Feb 3;11(8):2123-2132. doi: 10.7150/jca.34981. PMID: 32127939; PMCID: PMC7052937. 2. Huang S, Li C, Zhang X, Pan J, Li F, Lv Y, Huang J, Ling Q, Ye W, Mao S, Huang X, Jin J. Abivertinib synergistically strengthens the anti-leukemia activity of venetoclax in acute myeloid leukemia in a BTK-dependent manner. Mol Oncol. 2020 Oct;14(10):2560-2573. doi: 10.1002/1878-0261.12742. Epub 2020 Jul 3. PMID: 32519423; PMCID: PMC7530784.
In vivo protocol: 1. Huang S, Yu M, Shi N, Zhou Y, Li F, Li X, Huang X, Jin J. Apigenin and Abivertinib, a novel BTK inhibitor synergize to inhibit diffuse large B-cell lymphoma in vivo and vitro. J Cancer. 2020 Feb 3;11(8):2123-2132. doi: 10.7150/jca.34981. PMID: 32127939; PMCID: PMC7052937. 2. Huang S, Li C, Zhang X, Pan J, Li F, Lv Y, Huang J, Ling Q, Ye W, Mao S, Huang X, Jin J. Abivertinib synergistically strengthens the anti-leukemia activity of venetoclax in acute myeloid leukemia in a BTK-dependent manner. Mol Oncol. 2020 Oct;14(10):2560-2573. doi: 10.1002/1878-0261.12742. Epub 2020 Jul 3. PMID: 32519423; PMCID: PMC7530784.

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This message contains search results from the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM). Do not reply directly to this message

Sent On: Wed May 06 16:08:32 2020

12 selected items

PubMed Results
Items 1-12 of 12 (Display the 12 citations in PubMed)

1: Huang S, Yu M, Shi N, Zhou Y, Li F, Li X, Huang X, Jin J. Apigenin and Abivertinib, a novel BTK inhibitor synergize to inhibit diffuse large B-cell lymphoma in vivo and vitro. J Cancer. 2020 Feb 3;11(8):2123-2132. doi: 10.7150/jca.34981. PMID: 32127939; PMCID: PMC7052937.

2: Wang H, Pan R, Zhang X, Si X, Wang M, Zhang L. Abivertinib in patients with T790M-positive advanced NSCLC and its subsequent treatment with osimertinib. Thorac Cancer. 2020 Mar;11(3):594-602. doi: 10.1111/1759-7714.13302. Epub 2020 Jan 14. PMID: 31943845; PMCID: PMC7049520.

3: Zheng X, Wang W, Zhang Y, Ma Y, Zhao H, Gao H, Hu P, Jiang J. Development of an LC-MS/MS method for quantifying two main metabolites of abivertinib in human plasma. Biomed Chromatogr. 2020 Feb;34(2):e4704. doi: 10.1002/bmc.4704. Epub 2019 Dec 23. PMID: 31629371.

4: Yao X, Du N, Hu S, Wang L, Gao J. Rapid advances in research on and development of anticancer drugs in China. Biosci Trends. 2019 Nov 13;13(5):461-463. doi: 10.5582/bst.2019.01243. Epub 2019 Sep 10. PMID: 31511442.

5: Huang S, Pan J, Jin J, Li C, Li X, Huang J, Huang X, Yan X, Li F, Yu M, Hu C, Jin J, Xu Y, Ling Q, Ye W, Wang Y, Jin J. Abivertinib, a novel BTK inhibitor: Anti-Leukemia effects and synergistic efficacy with homoharringtonine in acute myeloid leukemia. Cancer Lett. 2019 Oct 1;461:132-143. doi: 10.1016/j.canlet.2019.07.008. Epub 2019 Jul 13. PMID: 31310800.

6: Zhang YC, Chen ZH, Zhang XC, Xu CR, Yan HH, Xie Z, Chuai SK, Ye JY, Han-Zhang H, Zhang Z, Bai XY, Su J, Gan B, Yang JJ, Li WF, Tang W, Luo FR, Xu X, Wu YL, Zhou Q. Analysis of resistance mechanisms to abivertinib, a third-generation EGFR tyrosine kinase inhibitor, in patients with EGFR T790M-positive non-small cell lung cancer from a phase I trial. EBioMedicine. 2019 May;43:180-187. doi: 10.1016/j.ebiom.2019.04.030. Epub 2019 Apr 23. PMID: 31027916; PMCID: PMC6558024.

7: Roskoski R Jr. Small molecule inhibitors targeting the EGFR/ErbB family of protein-tyrosine kinases in human cancers. Pharmacol Res. 2019 Jan;139:395-411. doi: 10.1016/j.phrs.2018.11.014. Epub 2018 Nov 27. PMID: 30500458.

8: Attwa MW, Kadi AA, Abdelhameed AS. Reactive intermediates and bioactivation pathways characterization of avitinib by LC-MS/MS: In vitro metabolic investigation. J Pharm Biomed Anal. 2019 Feb 5;164:659-667. doi: 10.1016/j.jpba.2018.11.033. Epub 2018 Nov 17. PMID: 30472584.

9: Wang H, Zhang L, Hu P, Zheng X, Si X, Zhang X, Wang M. Penetration of the blood-brain barrier by avitinib and its control of intra/extra-cranial disease in non-small cell lung cancer harboring the T790M mutation. Lung Cancer. 2018 Aug;122:1-6. doi: 10.1016/j.lungcan.2018.05.010. Epub 2018 May 21. PMID: 30032814.

10: Ma Y, Zheng X, Zhao H, Fang W, Zhang Y, Ge J, Wang L, Wang W, Jiang J, Chuai S, Zhang Z, Xu W, Xu X, Hu P, Zhang L. First-in-Human Phase I Study of AC0010, a Mutant-Selective EGFR Inhibitor in Non-Small Cell Lung Cancer: Safety, Efficacy, and Potential Mechanism of Resistance. J Thorac Oncol. 2018 Jul;13(7):968-977. doi: 10.1016/j.jtho.2018.03.025. Epub 2018 Apr 4. PMID: 29626621.

11: Wang W, Zheng X, Wang H, Wang L, Jiang J, Hu P. Development of an UPLC-MS/MS method for quantification of Avitinib (AC0010) and its five metabolites in human cerebrospinal fluid: Application to a study of the blood-brain barrier penetration rate of non-small cell lung cancer patients. J Pharm Biomed Anal. 2017 May 30;139:205-214. doi: 10.1016/j.jpba.2017.02.057. Epub 2017 Mar 4. PMID: 28285073.

12: Xu X. Parallel phase 1 clinical trials in the US and in China: accelerating the test of avitinib in lung cancer as a novel inhibitor selectively targeting mutated EGFR and overcoming T790M-induced resistance. Chin J Cancer. 2015 Jul 8;34(7):285-7. doi: 10.1186/s40880-015-0029-3. PMID: 26152224; PMCID: PMC4593347.



Additional Information

Resistance to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) presents a major clinical challenge in advanced non-small cell lung cancer (NSCLC).