Ibrutinib
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MedKoo CAT#: 202171

CAS#: 936563-96-1

Description: Ibrutinib, also known as PCI-32765, is a potent and orally active BTK inhibitor. Ibrutinib binds to and inhibits BTK activity, preventing B-cell activation and B-cell-mediated signaling and inhibiting the growth of malignant B cells that overexpress BTK. Ibrutinib was approved by the US FDA on November 13, 2013 for the treatment of mantle cell lymphoma.


Chemical Structure

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Ibrutinib
CAS# 936563-96-1

Theoretical Analysis

MedKoo Cat#: 202171
Name: Ibrutinib
CAS#: 936563-96-1
Chemical Formula: C25H24N6O2
Exact Mass: 440.19607
Molecular Weight: 440.49706
Elemental Analysis: C, 68.17; H, 5.49; N, 19.08; O, 7.26

Price and Availability

Size Price Availability Quantity
200.0mg USD 90.0 Same day
500.0mg USD 150.0 Same day
1.0g USD 250.0 Same day
2.0g USD 450.0 Same day
5.0g USD 750.0 Same day
10.0g USD 1250.0 Same day
20.0g USD 1850.0 Same day
50.0g USD 3250.0 Same day
500.0g USD 8950.0 2 Weeks
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Synonym: PCI32765, PCI-32765, PCI 32765, Ibrutinib, Imbruvica

IUPAC/Chemical Name: (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one.

InChi Key: XYFPWWZEPKGCCK-GOSISDBHSA-N

InChi Code: InChI=1S/C25H24N6O2/c1-2-21(32)30-14-6-7-18(15-30)31-25-22(24(26)27-16-28-25)23(29-31)17-10-12-20(13-11-17)33-19-8-4-3-5-9-19/h2-5,8-13,16,18H,1,6-7,14-15H2,(H2,26,27,28)/t18-/m1/s1

SMILES Code: C=CC(N1C[C@H](N2N=C(C3=CC=C(OC4=CC=CC=C4)C=C3)C5=C(N)N=CN=C52)CCC1)=O

Appearance: white 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 at 80 mg / mL

Shelf Life: >5 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: Ibrutinib (PCI-32765) is a Btk inhibitor with an IC50 of 0.5 nM.
In vitro activity: To better understand the mechanism of ibrutinib in bleeding events, platelet-rich plasma was isolated from healthy donors (n = 8) and donors with conditions associated with impaired platelet function or with potentially increased bleeding risk (on hemodialysis, taking aspirin, or taking warfarin; n = 8 each cohort) and light transmission aggregometry was used to assess platelet aggregation in vitro after exposure to escalating concentrations of ibrutinib, spanning and exceeding the pharmacologic range of clinical exposure. Platelet aggregation was induced by agonists of 5 major platelet receptors: adenosine diphosphate (ADP), thrombin receptor-activating peptide 6 (TRAP6), ristocetin, collagen, or arachidonic acid (AA). Platelet aggregation induced by ADP, TRAP6, ristocetin, and AA was not meaningfully inhibited by the maximal concentrations of ibrutinib (10 µM). In contrast, collagen-induced platelet aggregation was dose-dependently inhibited by ibrutinib in all donor cohorts (maximum aggregation % with 10 μM ibrutinib, -64% to -83% of agonist activity compared to control agonist samples but without ibrutinib). Reference: Hematology. 2020 Dec;25(1):112-117. https://www.tandfonline.com/doi/full/10.1080/16078454.2020.1730080
In vivo activity: The efficacy of ibrutinib in a dose dependent manner on tumor progression and survival was evaulated. Ibrutinib (12.5 mg/kg) treated mice had a significantly prolonged survival compared to phosphate-buffered saline (PBS) control mice (p < 0.02) with median survival of mice following ibrutinib treatment (32 days) compared to PBS control (24 days) (Figure 5A). The treatment experimental schema is shown in Figure 5B. Furthermore, a significant decrease of tumor progression was observed by measuring tumor luminescence signal intensity following ibrutinib treated Raji BL (Burkitt lymphoma) xenografted NSG mice at day 20 (p < 0.001) and at day 25 (p < 0.05) compared to control (Figure 5C and 5D). Reference: Oncoimmunology. 2018 Oct 11;8(1):e1512455. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287791/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMF 30.0 68.1
DMSO 48.01 108.99
DMSO:PBS (pH 7.2) (1:3) 0.25 0.57
Ethanol 0.25 0.57

Preparing Stock Solutions

The following data is based on the product molecular weight 440.49706 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. Ninomoto J, Mokatrin A, Kinoshita T, Marimpietri C, Barrett TD, Chang BY, Sukbuntherng J, James DF, Crowther M. Effects of ibrutinib on in vitro platelet aggregation in blood samples from healthy donors and donors with platelet dysfunction. Hematology. 2020 Dec;25(1):112-117. doi: 10.1080/16078454.2020.1730080. PMID: 32131714. 2. Nam HY, Nam JH, Yoon G, Lee JY, Nam Y, Kang HJ, Cho HJ, Kim J, Hoe HS. Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice. J Neuroinflammation. 2018 Sep 19;15(1):271. doi: 10.1186/s12974-018-1308-0. PMID: 30231870; PMCID: PMC6145206. 3. Chu Y, Lee S, Shah T, Yin C, Barth M, Miles RR, Ayello J, Morris E, Harrison L, Van de Ven C, Galardy P, Goldman SC, Lim MS, Hermiston M, McAllister-Lucas LM, Giulino-Roth L, Perkins SL, Cairo MS. Ibrutinib significantly inhibited Bruton's tyrosine kinase (BTK) phosphorylation,in-vitro proliferation and enhanced overall survival in a preclinical Burkitt lymphoma (BL) model. Oncoimmunology. 2018 Oct 11;8(1):e1512455. doi: 10.1080/2162402X.2018.1512455. PMID: 30546948; PMCID: PMC6287791. 4. Nam HY, Nam JH, Yoon G, Lee JY, Nam Y, Kang HJ, Cho HJ, Kim J, Hoe HS. Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice. J Neuroinflammation. 2018 Sep 19;15(1):271. doi: 10.1186/s12974-018-1308-0. PMID: 30231870; PMCID: PMC6145206.
In vitro protocol: 1. Ninomoto J, Mokatrin A, Kinoshita T, Marimpietri C, Barrett TD, Chang BY, Sukbuntherng J, James DF, Crowther M. Effects of ibrutinib on in vitro platelet aggregation in blood samples from healthy donors and donors with platelet dysfunction. Hematology. 2020 Dec;25(1):112-117. doi: 10.1080/16078454.2020.1730080. PMID: 32131714. 2. Nam HY, Nam JH, Yoon G, Lee JY, Nam Y, Kang HJ, Cho HJ, Kim J, Hoe HS. Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice. J Neuroinflammation. 2018 Sep 19;15(1):271. doi: 10.1186/s12974-018-1308-0. PMID: 30231870; PMCID: PMC6145206.
In vivo protocol: 1. Chu Y, Lee S, Shah T, Yin C, Barth M, Miles RR, Ayello J, Morris E, Harrison L, Van de Ven C, Galardy P, Goldman SC, Lim MS, Hermiston M, McAllister-Lucas LM, Giulino-Roth L, Perkins SL, Cairo MS. Ibrutinib significantly inhibited Bruton's tyrosine kinase (BTK) phosphorylation,in-vitro proliferation and enhanced overall survival in a preclinical Burkitt lymphoma (BL) model. Oncoimmunology. 2018 Oct 11;8(1):e1512455. doi: 10.1080/2162402X.2018.1512455. PMID: 30546948; PMCID: PMC6287791. 2. Nam HY, Nam JH, Yoon G, Lee JY, Nam Y, Kang HJ, Cho HJ, Kim J, Hoe HS. Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice. J Neuroinflammation. 2018 Sep 19;15(1):271. doi: 10.1186/s12974-018-1308-0. PMID: 30231870; PMCID: PMC6145206.

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1: Molica S. The emerging role of ibrutinib in the treatment of chronic lymphocytic leukemia. Expert Rev Hematol. 2013 Oct;6(5):543-6. doi: 10.1586/17474086.2013.831324. Epub 2013 Oct 2. PubMed PMID: 24083545.

2: Rushworth SA, MacEwan DJ, Bowles KM. Ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Sep 26;369(13):1277-8. doi: 10.1056/NEJMc1309710#SA2. PubMed PMID: 24066760.

3: Neffendorf JE, Gout I, Hildebrand GD. Ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Sep 26;369(13):1277. doi: 10.1056/NEJMc1309710#SA1. PubMed PMID: 24066759.

4: Byrd JC, O'Brien S, James DF. Ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Sep 26;369(13):1278-9. doi: 10.1056/NEJMc1309710. PubMed PMID: 24066758.

5: Cinar M, Hamedani F, Mo Z, Cinar B, Amin HM, Alkan S. Bruton tyrosine kinase is commonly overexpressed in mantle cell lymphoma and its attenuation by Ibrutinib induces apoptosis. Leuk Res. 2013 Oct;37(10):1271-7. doi: 10.1016/j.leukres.2013.07.028. Epub 2013 Aug 17. PubMed PMID: 23962569.

6: Akinleye A, Chen Y, Mukhi N, Song Y, Liu D. Ibrutinib and novel BTK inhibitors in clinical development. J Hematol Oncol. 2013 Aug 19;6:59. doi: 10.1186/1756-8722-6-59. PubMed PMID: 23958373; PubMed Central PMCID: PMC3751776.

7: Chang BY, Francesco M, De Rooij MF, Magadala P, Steggerda SM, Huang MM, Kuil A, Herman SE, Chang S, Pals ST, Wilson W, Wiestner A, Spaargaren M, Buggy JJ, Elias L. Egress of CD19(+)CD5(+) cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. Blood. 2013 Oct 3;122(14):2412-24. doi: 10.1182/blood-2013-02-482125. Epub 2013 Aug 12. PubMed PMID: 23940282; PubMed Central PMCID: PMC3790509.

8: Jain N, O'Brien S. Ibrutinib (PCI-32765) in chronic lymphocytic leukemia. Hematol Oncol Clin North Am. 2013 Aug;27(4):851-60, x. doi: 10.1016/j.hoc.2013.01.006. PubMed PMID: 23915749.

9: Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y, Hessler JD, Liu TM, Chang BY, Larkin KM, Stefanovski MR, Chappell DL, Frissora FW, Smith LL, Smucker KA, Flynn JM, Jones JA, Andritsos LA, Maddocks K, Lehman AM, Furman R, Sharman J, Mishra A, Caligiuri MA, Satoskar AR, Buggy JJ, Muthusamy N, Johnson AJ, Byrd JC. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood. 2013 Oct 10;122(15):2539-49. doi: 10.1182/blood-2013-06-507947. Epub 2013 Jul 25. PubMed PMID: 23886836; PubMed Central PMCID: PMC3795457.

10: Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, Grant B, Sharman JP, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Sukbuntherng J, Chang BY, Clow F, Hedrick E, Buggy JJ, James DF, O'Brien S. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Jul 4;369(1):32-42. doi: 10.1056/NEJMoa1215637. Epub 2013 Jun 19. PubMed PMID: 23782158; PubMed Central PMCID: PMC3772525.



Additional Information

Ibrutinib is a potent covalent kinase inhibitor that targets BTK. BTK, or Bruton's tyrosine kinase, is an obvious target for therapy of B cell diseases because inactivating mutations lead to B cell aplasia in humans and the disease X-linked agammaglobulinemia. Ibrutinib has modest cytotoxicity against CLL cells in vitro but also blocks trophic stimuli from the microenvironment. As with other inhibitors of the BCR pathway, ibrutinib causes rapid nodal reduction and response associated with rapid increase in lymphocytosis, which then returns to baseline over time. The ORR of ibrutinib in relapsed refractory CLL is 67 % with PFS 88 % at 15 months. In a cohort of untreated patients 65 years and over, the estimated 15 month PFS is 96 %. Registration trials have been initiated, and the difficult task that remains is to determine where in the course of CLL therapy this drug will have the greatest impact and benefit for patients. (source: Curr Hematol Malig Rep. 2013 Mar;8(1):1-6. ).