Small-molecule activation of the tumor suppressor kinase LKB1 via the pseudokinase STRAD.

The ability to target oncogenic signals has transformed oncology. Targeted therapies typically inhibit oncogenic kinases and GTPases. Therapeutic augmentation of tumor-suppressive signaling could be a viable alternative but poses challenges. Specifically, designing compounds capable of stimulating kinase activity is more challenging than inhibitor design, and most kinases lack identified allosteric pockets that could be exploited for the development of allosteric activators. Inactivation of the tumor suppressor kinase liver kinase B1 (LKB1) is associated with poor prognosis and therapeutic resistance. Thus, augmented LKB1 function could be beneficial for cancer patients whose tumors retain intact copies of the gene. LKB1 signals as part of an obligate trimer including the scaffolding protein MO25 and the pseudokinase STE20-related kinase adapter protein (STRAD). As STRAD binds to but does not metabolize ATP, it provides a defined nucleotide binding pocket that may be targeted for an allosteric activation strategy. We have developed STRAD-binding compounds capable of activating LKB1 to augment tumor-suppressive signaling and reduce viability in cancer cell lines.