The rise of targeting chimeras (TACs): next-generation medicines that preempt cellular events

Traditional targets and modalities that have provided rich substrates for medicine design and decades of productive industrial and academic research are not the primary drug discovery engines of the future. There is a steady shift in the target and modality landscape. Novel modalities such as protein degradation are an intense and hot area of research. The explosion of proximity induced ubiquitination of targets and proteasome or lysosome mediated degradation by expropriating E3 ligases (PROTACS, LYTACS) has inspired a number of other proximity induced post-translational modifications such as de-ubiquitination (DUBTACS), phosphorylation (PHICS), de-phosphorylation (PHORCS), acetylation (AceTAGs) to name a few. This review article of emerging TACs (targeting chimeras) provides a sampling of some of the chimeric molecules that preempt these cellular events and highlight opportunities and challenges for prospective medicine design and scientific research.