BTK

IBT6A (compound 14) is capable of producing ibrutinib as well as ibrutinib-based activity probes (ABP) [3].

[1]. A QUALITY BY DESIGN APPROACH FOR DEVELOPMENT OF SIMPLE AND ROBUST REVERSED PHASE STABILITY INDICATING HPLC METHOD FOR ESTIMATION OF IBRUTINIB AND ITS IMPURITIES.

[2]. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13075-80.

[3]. Direct and two-step bioorthogonal probes for Bruton's tyrosine kinase based on ibrutinib: a comparative study. Org Biomol Chem. 2015 May 14;13(18):5147-57.

Ibrutinib is a covalent and irreversible Bruton's tyrosine kinase (BTK) inhibitor that has been approved for the treatment of hematologic malignancies such as chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström macroglobulinemia. The covalent and irreversible nature of its molecular mechanism of action makes it possible to identify and monitor its targets in activity-based proteomic analysis (ABPP). In recent years, fluorescently labeled and biotinylated ibrutinib derivatives have appeared in the literature for in vitro and in vivo monitoring of BTK. The work described herein complements existing methods and involves a comparative study of the effectiveness of direct and two-step bioorthogonal ABPP for BTK. [3]

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Activation of the B cell antigen receptor (BCR) signaling pathway contributes to the development and maintenance of B cell malignancies and autoimmune diseases. Bruton's tyrosine kinase (Btk) is essential for BCR signaling, as evidenced by Btk dysfunctional mutations in humans and mice that prevent B cells from maturing at steps requiring a functional BCR pathway. This article introduces a selective and irreversible Btk inhibitor, PCI-32765, which is currently undergoing clinical development in patients with B-cell non-Hodgkin lymphoma. We used this inhibitor to investigate the biological effects of Btk inhibition on mature B-cell function and the progression of B-cell-related diseases. PCI-32765 blocks BCR signaling in human peripheral blood B cells at concentrations that do not affect T-cell receptor signaling. In a mouse model of collagen-induced arthritis, oral administration of PCI-32765 reduced circulating autoantibody levels and completely inhibited disease progression. PCI-32765 also inhibited autoantibody production and the development of kidney disease in an MRL-Fas(lpr) lupus model. Using a Btk fluorescent affinity probe, the occupancy of the Btk active site by PCI-32765 was monitored in vitro and in vivo. Occupancy of the Btk active site was closely related to the blockade of the BCR signaling pathway and the in vivo therapeutic effect. Furthermore, PCI-32765 induced an objective clinical response in dogs with spontaneous B-cell non-Hodgkin lymphoma. These findings support Btk inhibition as a therapeutic strategy for treating human diseases associated with BCR pathway activation. [2]

C22H22N6O

386.4497

386.186

1412418-47-3

IBT6A;1022150-12-4;IBT6A hydrochloride;1553977-42-6;(Rac)-IBT6A hydrochloride;1807619-60-8

67095487

White to off-white solid powder

4.702

2

6

4

29

521

0

O(C1C([H])=C([H])C([H])=C([H])C=1[H])C1C([H])=C([H])C(=C([H])C=1[H])C1C2=C(N([H])[H])N=C([H])N=C2N(C2([H])C([H])([H])N([H])C([H])([H])C([H])([H])C2([H])[H])N=1

GPSQYTDPBDNDGI-UHFFFAOYSA-N

InChI=1S/C22H22N6O/c23-21-19-20(15-8-10-18(11-9-15)29-17-6-2-1-3-7-17)27-28(22(19)26-14-25-21)16-5-4-12-24-13-16/h1-3,6-11,14,16,24H,4-5,12-13H2,(H2,23,25,26)

3-(4-phenoxyphenyl)-1-piperidin-3-ylpyrazolo[3,4-d]pyrimidin-4-amine

Btk inhibitor 1; 1412418-47-3; (Rac)-IBT6A; 3-(4-Phenoxy-phenyl)-1-piperidin-3-yl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine; 3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-(4-phenoxyphenyl)-1-piperidin-3-ylpyrazolo[3,4-d]pyrimidin-4-amine; 3-(4-phenoxyphenyl)-1-(3-piperidyl)pyrazolo[3,4-d]pyrimidin-4-ami ne; MFCD20482137;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~129.38 mM)

Solubility in Formulation 1: ≥ 1.67 mg/mL (4.32 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 1.67 mg/mL (4.32 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 1.67 mg/mL (4.32 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)