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Bruton's tyrosine kinase (Btk or BTK) is a kinase that plays a crucial role in B-cell development. BTK plays a crucial role in B cell maturation as well as mast cell activation through the high-affinity IgE receptor. BTK has emerged as a promising drug target for multiple diseases, particularly haematopoietic malignancies and autoimmune diseases related to B lymphocytes. Considerable progress has been made in the development of irreversible inhibitors, most of which target the SH3 pocket and the cysteine 481 residue of BTK.

Ibrutinib, a first-in-class BTK inhibitor, has demonstrated high response rates in both relapsed/refractory and treatment naïve chronic lymphocytic leukemia (CLL). However, scientists identified a structurally novel mutation (BTKT316A) in the SH2 domain, but not kinase domain, of Bruton tyrosine kinase which was associated with disease relapse.

Acalabrutinib (ACP-196) demonstrated higher biochemical and cellular selectivity than ibrutinib and spebrutinib. Acalabrutinib is a BTK inhibitor with key pharmacologic differentiators versus ibrutinib and spebrutinib and is currently being evaluated in clinical trials. More BTK inhibitors (GDC-0834, CGI-560, CGI-1746, HM-71224, CC-292, and ONO-4059, CNX-774, LFM-A13) are under inverstigation in the treatment of B-cell malignancies and autoimmune disorders.

 

References:

1. Winer ES, et al. Expert Opin Investig Drugs. 2012 Mar;21(3):355-61.

2. Kharfan-Dabaja MA, et al. Leukemia. 2014 Mar;28(3):507-17.

3. Aw A, et al. Drugs Aging. 2017 Jul;34(7):509-527.

4. Sharma S, et al. Oncotarget. 2016 Oct 18;7(42):68833-68841.

5. Barf T, et al. J Pharmacol Exp Ther. 2017 Nov;363(2):240-252.

Cat. No. Product Name CAS No. Information
PC-35328

ARQ-531

2095393-15-8

ARQ-531 (ARQ531) is a potent, reversible, orally available inhibitor of both wild type and C481S-mutant BTK kinase with IC50 of 0.85 and 0.39 nM, respectively; also ptently inhibits 45 kinases with >50% inhibition at 200 nM (TEC, BMX, LCK, TRK family kinases etc.); does not require the C481S residue to bind to BTK, inhibits CD69 expression on CD20+ B-cells with IC50 of 42 nM (Ibrutinib, IC50=3 nM); ARQ-531 inhibits proliferation of malignant cells both sensitive and resistant to ibrutinib (SUDHL6 Cell GI50=80 nM), ARQ 531 is superior to Ibrutinib in a TCL1 highly predictive adoptive transfer model of CLL.

Blood Cancer

Phase 1 Clinical

PC-63295

BMS-986195

1912445-55-6

BMS-986195 (BMS986195) is a novel potent, selective, covalent, irreversible inhibitor of Bruton’s tyrosine kinase (BTK), >5,000-fold selective over all kinases outside of the Tec family, and selectivity ranges 9- to 1010-fold within the Tec family; potently inhibits antigen-dependent interleukin-6 production, CD86 expression and proliferation in B cells (IC50<1 nM); demonstrates robust efficacy in murine models of RA including CIA and CAIA, protecting against clinically evident disease, histologic joint damage and bone mineral density loss.

Rheumatoid Arthritis

Phase 1 Clinical

PC-62583

PRN 1008

1575596-29-0

PRN1008 is a novel reversible, covalent and oral inhibitor of BTK with biochemical IC50 of 1.3 nM.

PC-60536

Poseltinib

1353552-97-2

Poseltinib (HM-71224, LY-3337641) is a potent and selective, covalent inhibitor of Btk with IC50 of 1.95 nM; also inhibits BMX, TEC, TXK, EGFR in biochemical sense (IC50=0.3-2.5 nM); effectively inhibits the phosphorylation of Btk and PLCγ2, and inhibits expression of CD40, CD69, and CD86 by activated primary human B cells with IC50 of 4.2, 4.2, and 7.7 nM, respectively; inhibited the production of TNF-α, IL-6, and IL-1β by human monocytes, and osteoclast formation by human monocytes; ameliorates arthritis in a mouse model.

Rheumatoid Arthritis

Phase 1 Clinical

PC-60535

(S)-Zanubrutinib

1691249-45-2

(S)-Zanubrutinib (BGB3111) is a potent, selective and orally available Btk inhibitor; shows much more restricted off-target activities against a panel of kinases, including ITK, compared with Ibrutinib; demonstrates nanomolar BTK inhibition activity, inhibits BCR aggregation-triggered BTK autophosphorylation, blocks downstream PLC-γ2 signaling, and potently inhibits cell proliferation in several MCL and DLBCL cell lines; demonstrates better anti-tumor activity than ibrutinib in TMD-8 subcutaneous xenograft model.

PC-50001

Vecabrutinib

1510829-06-7

Vecabrutinib (SNS-062) is a potent, reversible, non-covalent BTK inhibitor with IC50 of 2.9 and 4.4 nM for WT BTK and C481S BTK, respectively;

Binds to Tec kinase family members BTK (Kd=0.3 nM) and ITK (Kd=2.2 nM), but not bind EGFR, active in vitro in cells with the C481S mutation;

Inhibits pBTK in human whole blood with IC50 of 50 nM, demonstrates favorable pharmacokinetic properties, shows potential for overcoming the ibrutinib resistance due to C481S mutantion in BTK.

Blood Cancer

Phase 2 Clinical

PC-60422

BMS-986142

1643368-58-4

BMS-986142 is a potent, selective and reversible BTK inhibitor with IC50 of 0.5 nM; displays 20-60-fold selectivity over Tec family kinases, >10,000-fold selectivity over JAK2; potently inhibits signaling and functional end points, including calcium flux (IC50=9 nM), production of cytokines, proliferation, and surface expression of CD86 (IC50=3-4 nM); potently inhibits BCR-stimulated expression of CD69 on B cells in human whole blood with IC50 of 90 nM; exhibits excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile.

Rheumatoid Arthritis

Phase 2 Clinical

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