Fig. 1.

(A) Catalytic inhibitors must occupy most of their intended kinase to achieve therapeutic efficacy (i.e., “occupancy-driven” pharmacology). Kinase gene amplification or overexpression can balance the equilibrium toward the accumulation of an uninhibited kinase pool, and cancer cells become resistant to treatment with catalytic inhibitors. (B) PROTACs are heterobifunctional molecules that bring into close proximity a protein (kinase) of interest with an E3 ubiquitin ligase. When the intended protein kinase and the ubiquitin ligase complex interact in the right orientation, and an “acceptor” lysine is available on the target surface, the protein kinase becomes polyubiquitinated and is targeted for proteasomal degradation (“event-driven” pharmacology). The PROTAC gets recycled to start a new degradation reaction. The CRL4-Cereblon ubiquitin ligase complex has been used as an example. (C) PROTACs can trigger multiple cycles of degradation and be efficacious therapies at low target-to-compound or substoichiometric ratios. For amplified kinases, the kinase will be eliminated over time, and therapeutic benefit will be achieved.