Gilteritinib
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MedKoo CAT#: 206139

CAS#: 1254053-43-4 (free base)

Description: Gilteritinib, also known as ASP2215, is a potent FLT3/AXL inhibitor, which showed potent antileukemic activity against AML with either or both FLT3-ITD and FLT3-D835 mutations. In invitro, among the 78 tyrosine kinases tested, ASP2215 inhibited FLT3, LTK, ALK, and AXL kinases by over 50% at 1 nM with an IC50 value of 0.29 nM for FLT3, approximately 800-fold more potent than for c-KIT, the inhibition of which is linked to a potential risk of myelosuppression. ASP2215 inhibited the growth of MV4-11 cells, which harbor FLT3-ITD, with an IC50 value of 0.92 nM, accompanied with inhibition of pFLT3, pAKT, pSTAT5, pERK, and pS6. ASP2215 decreased tumor burden in bone marrow and prolonged the survival of mice intravenously transplanted with MV4-11 cells. ASP2215 may have potential use in treating AML.


Chemical Structure

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Gilteritinib
CAS# 1254053-43-4 (free base)

Theoretical Analysis

MedKoo Cat#: 206139
Name: Gilteritinib
CAS#: 1254053-43-4 (free base)
Chemical Formula: C29H44N8O3
Exact Mass: 552.35364
Molecular Weight: 552.71
Elemental Analysis: C, 63.02; H, 8.02; N, 20.27; O, 8.68

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5.0g USD 9650.0 2 Weeks
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Related CAS #: 1254053-43-4 (free base)   1254053-84-3 (hemifumarate)    

Synonym: ASP-2215; ASP2215; ASP 2215; Gilteritinib.

IUPAC/Chemical Name: 6-ethyl-3-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide.

InChi Key: GYQYAJJFPNQOOW-UHFFFAOYSA-N

InChi Code: InChI=1S/C29H44N8O3/c1-4-23-28(31-20-9-17-40-18-10-20)34-29(26(33-23)27(30)38)32-21-5-6-24(25(19-21)39-3)37-11-7-22(8-12-37)36-15-13-35(2)14-16-36/h5-6,19-20,22H,4,7-18H2,1-3H3,(H2,30,38)(H2,31,32,34)

SMILES Code: O=C(C1=NC(CC)=C(NC2CCOCC2)N=C1NC3=CC=C(N4CCC(N5CCN(C)CC5)CC4)C(OC)=C3)N

Appearance: 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: Gilteritinib (ASP2215) is a potent and ATP-competitive FLT3/AXL inhibitor with IC50s of 0.29 nM/0.73 nM, respectively.
In vitro activity: Gilteritinib inhibits the activity of eight of the 78 tested kinases by over 50% at concentrations of either 1 nM (FLT3, LTK, ALK, and AXL) or 5 nM (TRKA, ROS, RET, and MER). The IC50s are 0.29 nM for FLT3 and 0.73 nM for AXL. Gilteritinib inhibits FLT3 at an IC50 that is approximately 800-fold more potent than the concentration required to inhibit c-KIT (230 nM). The antiproliferative activity of Gilteritinib is evaluated against MV4-11 and MOLM-13 cells, which endogenously express FLT3-ITD. After 5 days of treatment, Gilteritinib inhibits the growth of MV4-11 and MOLM-13 cells with mean IC50s of 0.92 nM (95% CI: 0.23-3.6 nM) and 2.9 nM (95% CI: 1.4-5.8 nM), respectively. Growth suppression of MV4-11 cells is accompanied by inhibition of FLT3 phosphorylation. Relative to vehicle control cells, phosphorylated FLT3 levels are 57%, 8%, and 1% after 2 h of treatment with 0.1 nM, 1 nM, and 10 nM Gilteritinib, respectively. In addition, doses as low as 0.1 nM or 1 nM result in the suppression of phosphorylated ERK, STAT5, and AKT, all of which are downstream targets of FLT3 activation. To investigate the effects of Gilteritinib on AXL inhibition, MV4-11 cells that expressed exogenous AXL are treated with Gilteritinib. At concentrations of 1 nM, 10 nM, and 100 nM for 4 h, Gilteritinib treatment decreases phosphorylated AXL levels by 38%, 29%, and 22%, respectively. Reference: Invest New Drugs. 2017 Oct;35(5):556-565. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/28516360/
In vivo activity: The maximal plasma concentrations of gilteritinib were observed 2 h after a single oral administration of gilteritinib at 1 mg/kg, 6 mg/kg, and 10 mg/kg to MV4–11 xenografted mice. By contrast, the maximal intratumor concentrations were observed 4 h (1 mg/kg) or 8 h (6 mg/kg and 10 mg/kg) after dosing. Cmax and AUCt in plasma and tumors increased with increasing doses between 1 mg/kg and 10 mg/kg. The concentration in tumors was higher than that in plasma at each time point (Fig. 2a–b, Table S3). Gilteritinib dose ranges for cell viability studies are presented in the online resource (Table S4). Phosphorylated FLT3 decreased by approximately 40% compared with control phosphorylation levels in tumor samples within 1 h after single oral administration of 1–10 mg/kg gilteritinib (Fig. 2c), indicating target inhibition by gilteritinib. The effect on tumor burden of inhibiting FLT3 phosphorylation was assessed following 28 days of once-daily oral administration of gilteritinib. Significant growth inhibition of MV4–11 tumors was observed at 1 mg/kg/day (63% inhibition; P < 0.05) and 3 mg/kg/day (80% inhibition; P < 0.01), and near-complete tumor regression was seen at 6 mg/kg/day (93%; P < 0.001) and 10 mg/kg/day (100%; P < 0.001) (Fig. 2e). Four of the six mice in the 6 mg/kg/day group experienced complete tumor regression; all six mice in the 10 mg/kg/day group experienced complete tumor regression. Body weight was not affected by treatment with gilteritinib at any tested dose (Fig. 2f). Reference: Invest New Drugs. 2017 Oct;35(5):556-565. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/28516360/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 10.0 18.09
Ethanol 6.0 10.86

Preparing Stock Solutions

The following data is based on the product molecular weight 552.71 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. Mori M, Kaneko N, Ueno Y, Yamada M, Tanaka R, Saito R, Shimada I, Mori K, Kuromitsu S. Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia. Invest New Drugs. 2017 Oct;35(5):556-565. doi: 10.1007/s10637-017-0470-z. Epub 2017 May 17. PMID: 28516360; PMCID: PMC5613053. 2. Li L, Lin L, Li M, Li W. Gilteritinib induces PUMA-dependent apoptotic cell death via AKT/GSK-3β/NF-κB pathway in colorectal cancer cells. J Cell Mol Med. 2020 Feb;24(3):2308-2318. doi: 10.1111/jcmm.14913. Epub 2019 Dec 27. PMID: 31881122; PMCID: PMC7011145.
In vivo protocol: 1. Mori M, Kaneko N, Ueno Y, Yamada M, Tanaka R, Saito R, Shimada I, Mori K, Kuromitsu S. Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia. Invest New Drugs. 2017 Oct;35(5):556-565. doi: 10.1007/s10637-017-0470-z. Epub 2017 May 17. PMID: 28516360; PMCID: PMC5613053. 2. Li L, Lin L, Li M, Li W. Gilteritinib induces PUMA-dependent apoptotic cell death via AKT/GSK-3β/NF-κB pathway in colorectal cancer cells. J Cell Mol Med. 2020 Feb;24(3):2308-2318. doi: 10.1111/jcmm.14913. Epub 2019 Dec 27. PMID: 31881122; PMCID: PMC7011145.

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1. Kuravi S, Cheng J, Fangman G, Polireddy K, McCormick S, Lin TL, Singh AK, Abhyankar S, Ganguly S, Welch DR, Jensen RA, McGuirk JP, Balusu R. Preclinical Evaluation of Gilteritinib on NPM1-ALK-Driven Anaplastic Large Cell Lymphoma Cells. Mol Cancer Res. 2021 May;19(5):913-920. doi: 10.1158/1541-7786.MCR-20-0738. Epub 2021 Jan 29. PMID: 33514657.

1: Yun HD, Nathan S, Larson M, Hussain MJ, Katz DA, Varma A, Miller I, Ustun C. Erythroid differentiation of myeloblast induced by gilteritinib in relapsed FLT3-ITD-positive acute myeloid leukemia. Blood Adv. 2019 Nov 26;3(22):3709-3712. doi: 10.1182/bloodadvances.2019000775. PubMed PMID: 31765477; PubMed Central PMCID: PMC6880901.

2: Sidaway P. Gilteritinib improves outcomes in AML. Nat Rev Clin Oncol. 2019 Nov 19. doi: 10.1038/s41571-019-0305-2. [Epub ahead of print] PubMed PMID: 31745291.

3: Smith CC, Levis MJ, Perl AE, Martinelli G, Neubauer A, Berman E, Montesinos P, Baer MR, Larson RA, Chou WC, Yokoyama H, Recher C, Yoon SS, Hill JE, Rosales M, Bahceci E. Emerging Mutations at Relapse in Patients with FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia Who Received Gilteritinib Therapy in the Phase 3 Admiral Trial. Blood. 2019 Nov 13;134(Supplement_1):14. doi: 10.1182/blood-2019-122620. PubMed PMID: 31723984.

4: Kawase T, Nakazawa T, Eguchi T, Tsuzuki H, Ueno Y, Amano Y, Suzuki T, Mori M, Yoshida T. Effect of Fms-like tyrosine kinase 3 (FLT3) ligand (FL) on antitumor activity of gilteritinib, a FLT3 inhibitor, in mice xenografted with FL-overexpressing cells. Oncotarget. 2019 Oct 22;10(58):6111-6123. doi: 10.18632/oncotarget.27222. eCollection 2019 Oct 22. PubMed PMID: 31692922; PubMed Central PMCID: PMC6817455.

5: Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-1740. doi: 10.1056/NEJMoa1902688. PubMed PMID: 31665578.

6: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Available from http://www.ncbi.nlm.nih.gov/books/NBK548423/ PubMed PMID: 31643742.

7: Zhao J, Song Y, Liu D. Correction to: Gilteritinib: a novel FLT3 inhibitor for acute myeloid leukemia. Biomark Res. 2019 Oct 17;7:21. doi: 10.1186/s40364-019-0172-0. eCollection 2019. PubMed PMID: 31636908; PubMed Central PMCID: PMC6796449.

8: Akahane D, Moriyama M, Yoshizawa S, Katagiri S, Fujimoto H, Gotoh A. Successful treatment with gilteritinib for initially FMS-like tyrosine kinase 3 gene internal tandem duplications-positive elderly refractory acute myeloid leukemia that changed into FMS-like tyrosine kinase 3 gene tyrosine kinase domain-positive after cord blood transplantation. Geriatr Gerontol Int. 2019 Oct;19(10):1063-1064. doi: 10.1111/ggi.13772. PubMed PMID: 31602758.

9: Zhao J, Song Y, Liu D. Gilteritinib: a novel FLT3 inhibitor for acute myeloid leukemia. Biomark Res. 2019 Sep 11;7:19. doi: 10.1186/s40364-019-0170-2. eCollection 2019. Review. Erratum in: Biomark Res. 2019 Oct 17;7:21. PubMed PMID: 31528345; PubMed Central PMCID: PMC6737601.

10: Saleh N. Gilteritinib Changes AML Landscape. Oncology (Williston Park). 2019 Aug 23;33(8). pii: 683729. PubMed PMID: 31469903.

11: McMahon CM, Perl AE. Gilteritinib for the treatment of relapsed and/or refractory FLT3-mutated acute myeloid leukemia. Expert Rev Clin Pharmacol. 2019 Sep;12(9):841-849. doi: 10.1080/17512433.2019.1657009. Epub 2019 Aug 27. Review. PubMed PMID: 31454267.

12: Ma J, Zhao S, Qiao X, Knight T, Edwards H, Polin L, Kushner J, Dzinic SH, White K, Wang G, Zhao L, Lin H, Wang Y, Taub JW, Ge Y. Inhibition of Bcl-2 Synergistically Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Preclinical Models of FLT3-Mutated Acute Myeloid Leukemia. Clin Cancer Res. 2019 Nov 15;25(22):6815-6826. doi: 10.1158/1078-0432.CCR-19-0832. Epub 2019 Jul 18. PubMed PMID: 31320594; PubMed Central PMCID: PMC6858954.

13: Weisberg E, Meng C, Case AE, Sattler M, Tiv HL, Gokhale PC, Buhrlage SJ, Liu X, Yang J, Wang J, Gray N, Stone RM, Adamia S, Dubreuil P, Letard S, Griffin JD. Comparison of effects of midostaurin, crenolanib, quizartinib, gilteritinib, sorafenib and BLU-285 on oncogenic mutants of KIT, CBL and FLT3 in haematological malignancies. Br J Haematol. 2019 Nov;187(4):488-501. doi: 10.1111/bjh.16092. Epub 2019 Jul 15. PubMed PMID: 31309543.

14: McMahon CM, Canaani J, Rea B, Sargent RL, Qualtieri JN, Watt CD, Morrissette JJD, Carroll M, Perl AE. Gilteritinib induces differentiation in relapsed and refractory FLT3-mutated acute myeloid leukemia. Blood Adv. 2019 May 28;3(10):1581-1585. doi: 10.1182/bloodadvances.2018029496. PubMed PMID: 31122910; PubMed Central PMCID: PMC6538870.

15: Ueno Y, Mori M, Kamiyama Y, Saito R, Kaneko N, Isshiki E, Kuromitsu S, Takeuchi M. Evaluation of gilteritinib in combination with chemotherapy in preclinical models of FLT3-ITD+ acute myeloid leukemia. Oncotarget. 2019 Apr 2;10(26):2530-2545. doi: 10.18632/oncotarget.26811. eCollection 2019 Apr 2. PubMed PMID: 31069015; PubMed Central PMCID: PMC6493465.

16: Gilteritinib Likely New Standard Care for AML. Cancer Discov. 2019 Jun;9(6):OF6. doi: 10.1158/2159-8290.CD-NB2019-046. Epub 2019 Apr 1. PubMed PMID: 30936061.

17: Dhillon S. Gilteritinib: First Global Approval. Drugs. 2019 Feb;79(3):331-339. doi: 10.1007/s40265-019-1062-3. Review. PubMed PMID: 30721452.

18: Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006-. Available from http://www.ncbi.nlm.nih.gov/books/NBK535606/ PubMed PMID: 30601615.

19: Usuki K, Sakura T, Kobayashi Y, Miyamoto T, Iida H, Morita S, Bahceci E, Kaneko M, Kusano M, Yamada S, Takeshita S, Miyawaki S, Naoe T. Clinical profile of gilteritinib in Japanese patients with relapsed/refractory acute myeloid leukemia: An open-label phase 1 study. Cancer Sci. 2018 Oct;109(10):3235-3244. doi: 10.1111/cas.13749. PubMed PMID: 30039554; PubMed Central PMCID: PMC6172068.

20: Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, Claxton D, Erba HP, Gill S, Goldberg S, Jurcic JG, Larson RA, Liu C, Ritchie E, Schiller G, Spira AI, Strickland SA, Tibes R, Ustun C, Wang ES, Stuart R, Röllig C, Neubauer A, Martinelli G, Bahceci E, Levis M. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 2017 Aug;18(8):1061-1075. doi: 10.1016/S1470-2045(17)30416-3. Epub 2017 Jun 20. Erratum in: Lancet Oncol. 2017 Dec;18(12 ):e711. Lancet Oncol. 2018 Jul;19(7):e335. Lancet Oncol. 2019 Jun;20(6):e293. PubMed PMID: 28645776; PubMed Central PMCID: PMC5572576.



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