PDBsum entry 6e4f

Signaling protein/inhibitor

PDB id: 6e4f

Contents

Protein chain

270 a.a.

Ligands

HRA

IMD ×2

EDO ×2

Waters ×414

PDB id:

6e4f

Name:

Signaling protein/inhibitor

Title:

Crystal structure of arq 531 in complex with the kinase domain of btk

Structure:

Tyrosine-protein kinase btk. Chain: a. Synonym: agammaglobulinemia tyrosine kinase,atk,b-cell progenitor kinase,bpk,bruton tyrosine kinase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: btk, agmx1, atk, bpk. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

1.15Å R-factor: 0.131 R-free: 0.150

Authors:

S.Eathiraj

Key ref:

S.D.Reiff et al. (2018). The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation. Cancer Discov, 8, 1300-1315. PubMed id: 30093506 DOI: 10.1158/2159-8290.CD-17-1409

Date:

17-Jul-18 Release date: 05-Sep-18

Protein chain

Q06187  (BTK_HUMAN) -  Tyrosine-protein kinase BTK from Homo sapiens

Seq: 659 a.a.

Struc: 270 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1158/2159-8290.CD-17-1409

Cancer Discov 8:1300-1315 (2018)

PubMed id: 30093506

The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation.

S.D.Reiff, R.Mantel, L.L.Smith, J.T.Greene, E.M.Muhowski, C.A.Fabian, V.M.Goettl, M.Tran, B.K.Harrington, K.A.Rogers, F.T.Awan, K.Maddocks, L.Andritsos, A.M.Lehman, D.Sampath, R.Lapalombella, S.Eathiraj, G.Abbadessa, B.Schwartz, A.J.Johnson, J.C.Byrd, J.A.Woyach.

ABSTRACT

Targeted inhibition of Bruton tyrosine kinase (BTK) with the irreversible inhibitor ibrutinib has improved outcomes for patients with hematologic malignancies, including chronic lymphocytic leukemia (CLL). Here, we describe preclinical investigations of ARQ 531, a potent, reversible inhibitor of BTK with additional activity against Src family kinases and kinases related to ERK signaling. We hypothesized that targeting additional kinases would improve global inhibition of signaling pathways, producing more robust responses. In vitro treatment of patient CLL cells with ARQ 531 decreases BTK-mediated functions including B-cell receptor (BCR) signaling, viability, migration, CD40 and CD86 expression, and NF-κB gene transcription. In vivo, ARQ 531 was found to increase survival over ibrutinib in a murine Eμ-TCL1 engraftment model of CLL and a murine Eμ-MYC/TCL1 engraftment model resembling Richter transformation. Additionally, ARQ 531 inhibits CLL cell survival and suppresses BCR-mediated activation of C481S BTK and PLCγ2 mutants, which facilitate clinical resistance to ibrutinib.Significance: This study characterizes a rationally designed kinase inhibitor with efficacy in models recapitulating the most common mechanisms of acquired resistance to ibrutinib. Reversible BTK inhibition is a promising strategy to combat progressive CLL, and multikinase inhibition demonstrates superior efficacy to targeted ibrutinib therapy in the setting of Richter transformation. Cancer Discov; 8(10); 1300-15. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1195.