On June 23, 2017 ArQule, Inc. (Nasdaq: ARQL) reported that preclinical data for ARQ 531 in diffuse large B-cell lymphoma (DLBCL) in vitro and in vivo tumor models was presented at EHA (Free EHA Whitepaper) Congress in Madrid, Spain (Press release, ArQule, JUN 23, 2017, View Source [SID1234519655]). ARQ 531 is an investigational, orally bioavailable, potent and reversible inhibitor of both wild type and C481S-mutant Bruton’s tyrosine kinase (BTK). Schedule your 30 min Free 1stOncology Demo! The presentation titled "ARQ 531, A Reversible BTK Inhibitor, Demonstrates Potent Anti-Tumor Activity in ABC-DLBCL and GCB-DLBCL" can be viewed at View Source
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ARQ 531 Poster Presentation Highlights
Preclinical data suggests ARQ 531 has the potential for broad clinical utility in a wide range of hematological malignancies and lymphomas.
The signaling pathways evaluated show a distinct kinase inhibition profile that could be advantageous in treating lymphomas.
ARQ 531, unlike other BTK inhibitors, has activity in both ABC-DLBCL and GCB-DLBCL preclinical models.
A phase 1 trial with ARQ 531 in patients with B-cell malignancies refractory to other therapeutic options, including ibrutinib, is planned to commence by the third quarter of 2017.
"This data further strengthens a very comprehensive preclinical package for ARQ 531," said Dr. Brian Schwartz, M.D., Head of Research and Development and Chief Medical Officer at ArQule. "While targeting ibrutinib resistant patients will be an initial, fast-to-market strategy for the clinical development of ARQ 531, the data presented at EHA (Free EHA Whitepaper) clearly demonstrate the potential clinical utility of the drug beyond ibrutinib refractory cancers."
B-cell malignancies, like chronic lymphocytic leukemia, Waldenstrom’s macroglobulinemia, DLBCL and mantle cell lymphoma are driven by BTK. The only approved BTK inhibitor, ibrutinib, is irreversible and makes a covalent bond with the C481 residue of the targeted protein. Although ibrutinib has demonstrated excellent responses in patients with elevated B-cell receptor signaling, clinical resistance has been observed, and the BTK C481S mutation is emerging as a predominant mechanism of resistance. As a reversible inhibitor, ARQ 531 does not require interaction with the C481 residue, a binding site essential for irreversible ibrutinib binding to BTK, thus positioning ARQ 531 as a targeted therapy for patients harboring C481S-mutant BTK who have developed resistance to irreversible BTK inhibitors.
About BTK and ARQ 531
ARQ 531 is an investigational, orally bioavailable, potent and reversible Bruton’s tyrosine kinase (BTK) inhibitor. Biochemical and cellular studies have shown that ARQ 531 inhibits both the wild type and C481S-mutant forms of BTK. The C481S mutation is a known emerging resistance mechanism for first generation irreversible BTK inhibitors. In preclinical studies ARQ 531 has demonstrated high oral bioavailability as well as good ADME, pharmacokinetic and metabolic properties. The company plans to initiate a phase 1 trial by the third quarter of 2017. BTK is a therapeutic target that has been clinically proven to inhibit B-cell receptor signaling in blood cancers.