Degraders: The Ultimate Weapon Against Amplified Driver Kinases in Cancer

Abstract

Amplification of pro-oncogenic kinases is a common genetic alteration driving tumorigenic phenotypes. Cancer cells rely on the amplified kinases to sustain cell proliferation, survival, and growth, presenting an opportunity to develop therapies targeting the amplified kinases. Utilizing small-molecule catalytic inhibitors as therapies to target amplified kinases is plagued by de novo resistance driven by increased expression of the target, and amplified kinases can drive tumorigenic phenotypes independent of catalytic activity. Here, we discuss the emergence of proteolysis-targeting chimeras that provide an opportunity to target these oncogenic drivers effectively. SignificanceProtein kinases contribute to tumorigenesis through catalytic and non-catalytic mechanisms, and kinase gene amplifications are well-described mechanisms of resistance to small-molecule catalytic inhibitors. Repurposing catalytic inhibitors for the development of protein degraders will offer improved clinical benefits by targeting non-catalytic functions of kinases that promote tumorigenesis and overcoming resistance due to amplification.

Measurement and utilization of the proteomic reactivity by mass spectrometry

“…Targeted RDP screening of cysteine‐reactive fragment library has identified covalent binders for RNF4, an E3 ligase, and optimized to degrade BRD4 as a model system (Ward et al, 2019). Covalent degraders have also been developed for BTK kinase degradation using ibrutinib as the targeting ligand (Torres‐Ayuso & Brognard, 2022). However, the large size of covalent PROTACs may limit their cell and blood‐brain barrier permeability.…”