Intrigued by the selectivity of the (Ra) atropisomer toward RET kinase, an emerging therapeutictarget fordiverse cancers,39−43 we set out to optimize these compounds for RET, quickly arrivingat compound (Ra)-23 (Figure 7A), whichpossesses low single-digit nM activity toward RET and orders-of-magnitudeselectivity for RET over other kinases (e.g., VEGFR, EGFR) whose off-targetinhibition is thought to be the source of adverse events in patients.44 This selectivity extended to cells in which(Ra)-2 possessed low μMactivities against models of RET-driven cancers (Figure 7B). The gene discussed is EGFR; the disease is cancer.