AP32788 is a tyrosine kinase inhibitor (TKI) designed to address an unmet medical need in a subset of non-small cell lung cancers. Using our targeted structure-based drug discovery methods, ARIAD’s research team worked to design and build this molecule and see it from concept to nomination in under a year –a testament to the process, science, and people involved in ARIAD’s drug discovery group.
In December 2014, we nominated AP32788 for clinical development. We filed an investigational new drug (IND) application for AP32788 at the end of 2015, and in February 2016 we announced that FDA had provided clearance to begin clinical development of AP32788.
In April 2016 we announced the results of comprehensive preclinical studies on AP32788, at the American Association for Cancer Research (AACR) Annual Meeting. The research conducted by ARIAD scientists showed that in a matched set of engineered cell lines, AP32788 inhibited all tested EGFR and HER2 mutants, including exon 20 insertion mutants, with selectivity over wild-type (WT) EGFR. Inhibition of WT EGFR in non-tumor cells has been associated with dose-limiting toxicities of EGFR inhibitors in patients. Enzymatic analysis confirmed that AP32788 irreversibly inactivated EGFR exon 20 with 20-fold selectivity over WT EGFR, in contrast to other tested EGFR TKIs. AP32788 also induced tumor regressions in a mouse EGFR exon 20 model at doses that were well tolerated.
The Phase 1/2 clinical trial of AP32788 is now open for patient enrollment.
AP32788 (gray) shown binding to its target.