ARQ 531 is an investigational, orally bioavailable, potent and reversible inhibitor of both wild type and C481S-mutant Bruton’s tyrosine kinase (BTK). We have conducted pre-clinical efficacy, toxicology and pharmacology studies and plan to file an Investigational New Drug (IND) application in Q1 2017 and begin a phase 1 trial by the Q3 of 2017.
B-cell malignancies, like chronic lymphocytic lymphoma (CLL), diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) 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 BCR signaling, clinical resistance has been observed, and the BTK C481S-mutation that prevents covalent binding of ibrutinib to BTK 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 potentially positioning ARQ 531 as a targeted therapy for CLL, DLBCL, MCL patients harboring C481S-mutant BTK who have developed resistance to irreversible BTK inhibitors.
Patients with tumors harboring the BTK C481S mutation could benefit from being targeted by ARQ 531, a potent inhibitor of that mutation.
Preliminary studies suggest an opportunity for clinical development of ARQ 531 in ibrutinib resistant cancers. We plan to begin clinical testing in Q2 2017.