AP26113 is a small molecule that in preclinical studies has exhibited activity as a potent tyrosine-kinase inhibitor of anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) and c-ros oncogene 1 (ROS1). Like Iclusig, AP26113 was internally discovered by ARIAD scientists, and targets unique genetic features of cancer cells.
ALK was first identified as a chromosomal rearrangement in anaplastic large-cell lymphoma (ALCL). Genetic studies indicate that abnormal expression of ALK is a key driver of certain types of non-small cell lung cancer (NSCLC) and neuroblastomas, as well as ALCL. Since ALK is generally not expressed in normal adult tissues, it represents a highly promising molecular target for cancer therapy.
EGFR is another validated target in NSCLC. Unfortunately, mutation-based resistance at the T790M “gatekeeper” position is observed in approximately 50 percent of patients taking first-generation EGFR inhibitors. While second-generation EGFR inhibitors are in development, clinical efficacy has been limited due to toxicity thought to be associated with native (endogenous or unmutated) EGFR inhibition. Therapies designed to target activated EGFR and the T790M mutation but avoiding native EGFR inhibition are another promising class of cancer therapeutics.
ROS1 is another validated molecular target in NSCLC. In preclinical studies, AP26113 was shown to inhibit ROS1 fusions as potently as it inhibited ALK, retaining activity against the gatekeeper mutation of ROS1, and suppressing the outgrowth of resistant ROS1 cells at clinically achievable levels.