On July 18, 2016 ArQule, Inc. (Nasdaq:ARQL) reported the first public presentation of data on its novel BTK inhibitor, ARQ 531, at the 2016 Pan Pacific Lymphoma Conference in Koloa, Hawaii (Press release, ArQule, JUL 18, 2016, View Source [SID:1234513933]). ARQ 531 is an investigational, orally bioavailable, potent and reversible Bruton’s tyrosine kinase (BTK) inhibitor.
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In preclinical testing, ARQ 531 demonstrated biochemical inhibition of both wild type and C481S-mutant BTK at sub-nanomolar levels and potent cellular inhibition in C481S-mutant BTK cells that are resistant to ibrutinib. This molecule also exhibits a distinct kinase selectivity profile with inhibitory activity against several key oncogenic drivers related to ibrutinib resistance. It is currently estimated that about 10% of patients treated with ibrutinib develop resistance with over 80% presenting the C481S mutation. This incidence rate is expected to increase.
Additionally, the compound potently suppresses cell proliferation of hematological malignancies in vitro, with B-cell receptor signaling inhibition. ARQ 531 also demonstrates strong in vivo target and pathway inhibition of phospho-BTK with potent and durable growth suppression.
"We are beginning to see increasing resistance to ibrutinib which is creating the need for a BTK inhibitor, like ARQ 531, that targets the C481S mutation," said Dr. Brian Schwartz, Head of Research and Development and Chief Medical Officer at ArQule. "The preclinical profile of ARQ 531 as a potent and reversible inhibitor of wild type and mutant BTK presents the potential for a first-in-class and best-in-class molecule. We are working toward completing GLP toxicology studies and filing an IND in early 2017."
The poster titled "ARQ 531, a Novel, Oral, Non-Covalent Inhibitor of Wild Type and C481S Mutant BTK with Potent Anti-Tumor Activity" can be viewed at View Source
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. ARQ 531 has high oral bioavailability as well as good ADME, pharmacokinetic and metabolic properties. The company plans to file an IND for ARQ 531 in early 2017. BTK is a therapeutic target that has been clinically proven to inhibit B-cell receptor signaling in blood cancers.