On August 13, 2018 ArQule, Inc. (Nasdaq:ARQL), reported the publication of preclinical study data for ARQ 531, the Company’s rationally-designed, reversible inhibitor of both wild type and C481S-mutant Bruton’s tyrosine kinase (BTK) (Press release, ArQule, AUG 13, 2018, View Source [SID1234532694]). The studies, published in Cancer Discovery, were conducted in collaboration with researchers at The Ohio State University. Data from these studies demonstrated efficacy in in vitro and in vivo hematologic malignancy models that recapitulate the most common mechanisms of resistance to irreversible BTK inhibitors, including ibrutinib.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Highlights from the manuscript (link here) include:

Differentiated Crystal Structure and Biochemical Profile

The crystal structure of ARQ 531 bound to BTK elucidates the mechanism of BTK inhibition that is not dependent on the specific amino acid residue at position 481 (eg. C or S)
Recombinant BTK biochemical assays of ARQ 531 and ibrutinib show similar inhibition for wild type BTK, however ibrutinib has dramatically lower inhibition, binding affinity and residence time for mutant BTK
"Relapsed and refractory patients that develop resistance to ibrutinib have poor outcomes and limited treatment options," said Brian Schwartz, M.D., Chief Medical Officer and Head of R&D at ArQule. "ARQ 531 was rationally-designed and selected to address this unmet need by inhibiting both wild type and mutant BTK. The published crystal structure and biochemistry clearly demonstrate the mechanism by which ARQ 531 maintains binding and inhibition of mutant BTK in conditions where ibrutinib cannot."

Established Activity in Multiple Cellular and Murine Models of Hematological Malignancies

Exhibited dose dependent toxicity in human primary CLL cells (mutant and wild type)
Inhibited CLL cell migration in vitro
Established superiority to ibrutinib in an engraftment murine model of CLL
Showed activity against other B-cell signaling pathways
Demonstrated efficacy in a murine model of Richter’s transformation
John Byrd, M.D., the Warren Brown Chair of Leukemia Research at The Ohio State University stated, "The inhibition profile of ARQ 531 may confer distinct advantages over ibrutinib, potentially expanding the patient population beyond those with a C481S mutation who may benefit from treatment. Targeting multiple kinases in the B cell activation pathway may provide more durable responses to treatment while also delaying the emergence of treatment resistance. Jennifer Woyach, M.D., Associate Professor of Medicine at The Ohio State University, added, "I am particularly encouraged by the CLL mouse model data which established the superior efficacy of ARQ 531 compared to ibrutinib and the efficacy of ARQ 531 in the model of Richter’s transformation as this is an extremely aggressive disease with very few treatment options."