ArQule presents preclinical data for ARQ 531

Data supports further preclinical and clinical research in BTK-sensitive and ibrutinib-resistant malignancies

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BURLINGTON, Mass.—ArQule, Inc. has announced the first public presentation of data on its novel BTK inhibitor, ARQ 531, at the 2016 Pan Pacific Lymphoma Conference in Koloa, Hawaii. ARQ 531 is an investigational orally bioavailable, potent and reversible Bruton’s tyrosine kinase (BTK) inhibitor.
The poster, entitled “ARQ 531, a Novel, Oral, Non-Covalent Inhibitor of Wild Type and C481S Mutant BTK with Potent Anti-Tumor Activity,” can be viewed at
In preclinical testing, ARQ 531 has 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. Current estimates suggest about 10 percent of patients treated with ibrutinib develop resistance, with over 80 percent presenting the C481S mutation. This incidence rate is expected to increase. Additionally, ARQ 531 potently suppresses cell proliferation of hematological malignancies in vitro, with B-cell receptor signaling inhibition. The compound 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.”
According to Schwartz, ARQ 531 was primarily designed to overcome ibrutinib resistance driven by the BTK-C481S and other BTK mutations. Now ArQule hopes that ARQ 531 may become a best-in-class second-generation BTK inhibitor targeting all BTK-driven malignancies.
“The BTK-C481S mutation is an acquired resistance mutation in patients who relapse following ibrutinib treatment, i.e., this mutation was not present before treatment with ibrutinib and was only detected following disease progression while in treatment,” Schwartz tells DDNews. “Cancer cells develop the C481S mutation to prevent irreversible covalent interaction with ibrutinib as a resistance mechanism to overcome BTK inhibition. Cancer cells are capable of generating diverse resistance mechanisms for a drug, and the high prevalence of the C481S mutation in ibrutinib refractory patients strongly indicates that BTK is an essential target for tumor growth.”
“Unlike ibrutinib, ARQ 531 is a reversible, non-covalent inhibitor of BTK, does not require the C481 residue to bind BTK and shows potent inhibitory activity against the acquired ibrutinib resistant C481S mutant of BTK,” Schwartz continues. “In addition to directly inhibiting BTK activation, it is capable of targeting key oncogenic signaling pathways important for the survival and migration of cancer cells. ARQ 531 has excellent efficacy in both in-vitro and in-vivo preclinical models where BTK is critical for tumor growth.”
“The initial hematological malignancy targeted [with ARQ 531] will be refractory chronic lymphocytic leukemia that is resistant to ibrutinib due to acquired BTK-C481S mutation. In addition, other malignancies where ibrutinib is active—such as mantle cell lymphoma, diffuse large B-cell lymphoma and Waldenstrom macroglobulinemia cancers—will also be targeted,” says Schwartz.
Asked if ARQ 531 could one day have resistance issues similar to those with ibrutinib, Schwartz responds, “It’s too early to say, but resistance is theoretically possible for most kinase inhibitors similar to ARQ 531. Following long-term exposure to most kinase inhibitors, cancer cells are capable of developing acquired resistance. However, with regard to BTK inhibition, ARQ 531 works with distinct mechanisms of target engagement that makes resistance less likely.”

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