Chimeric small molecule therapeutics are a class of drugs designed with multiple active domains to operate outside of the typical protein inhibition model. While most small molecule drugs inhibit target proteins by binding their active site, chimerics form protein-protein ternary structures to induce degradation or, less frequently, other protein modifications.
 Small molecule drugs, compounds typically <1 kD in mass, comprise a large portion of the therapeutic market. These drugs usually operate by agonizing or antagonizing the active site on a disease-linked protein of interest, though allosteric regulation is possible. With an estimated 93% of the human proteome lacking druggable binding sites, methods have been developed to modulate protein activity through binding of any available site rather than only the active site. These drugs contain a target protein binding warhead in addition to a linker-separated active domain. This domain may recruit a second protein to the proximity, induce protease-mediated degradation, or recruit a kinase for directed phosphorylation, among other functions. These drugs expand both the mechanism of action for small molecule therapeutics and the pool of potential protein targets.
 Proteolysis-targeting chimeras (PROTACs) were first reported by Kathleen Sakamoto, Craig Crews, and Raymond Deshaies in 2001. A chimeric molecule consisting of ovalicin (a MetAP-2 small molecule inhibitor) and IκBα phosphopeptide (a recruiter of the SCFβ-TRCP E3 ligase complex) separated by a linker was constructed and shown to induce MetAP-2 degradation in in vitro cell models. Further study confirmed that E3 ligase-mediated ubiquitination and subsequent proteasome degradation was responsible for reduced MetAP-2 levels. Continued work on this system by Craig Crews and others has expanded the potential pool of E3 ligases and degradation targets with Arvinas Inc. founded in 2013 to bring PROTAC drugs to market. As of April 2023, Arvinas has one drug in Stage 3 clinical trials (ARV-471, an estrogen receptor degrader), and two drugs in Stage 2 clinical trials (androgen receptor degraders ARV-110 and ARV-766) for treatment of breast and prostate cancer, respectively. Arvinas released Phase 2 clinical trial results for ARV-471 in December, 2022 reporting a clinical benefit rate of 40% in CDK4/6 inhibitor-pretreated patients and an absence of dose-limiting toxicities.
 Hydrophobic tag degraders contain a binding domain in addition to a linker-separated hydrophobic moiety, such as adamantyl, to induce protein degradation. As exposed hydrophobicity is characteristic of protein misfolding, the native cell proteasome may recognize and degrade proteins tagged with the hydrophobic moiety. Taavi Neklesa and Craig Crews first reported hydrophobic tag degradation in 2011 as a tool to probe protein function in conjunction with cognate HaloTag fusion proteins. This principle has also been further used to effectively degrade transcription factors (a traditionally difficult class to drug) and cancer-linked EZH2 in in vitro models. As of yet, no drug candidates have been publicly identified making use of this technology.
 Lysosome-targeting chimeras (LYTACs) have been developed, combining target-binding compounds or antibodies and glycopeptide ligands to stimulate the lysosomal degradation pathway. Unlike the proteasome pathway, this enables the targeted degradation of extracellular and membrane-bound proteins in addition to cytoplasmic ones. Autophagy-targeting chimeras (AUTACs) can be employed to degrade proteins as well as protein aggregates and organelles. AUTAC degradation tags are typically derived from guanine though the particular mechanism of action is still unclear. Autophagosome-tethering compounds (ATTECs) mimic this strategy, directly appending a target protein to the autophagosome membrane for degradation absent the use of a linker. Phosphorylation-inducing chimeric small molecules (PHICS) employ the warhead-linker-recruiter structure to direct phosphorylation of a given target by proximity to a desired kinase. This technique does not necessarily involve protein degradation and may instead be used to modulate protein function to direct or inhibit certain pathways. Further work in the Crews Lab has used chimeric oligonucleotides, the dCas9 protein, and chimeric small molecules to create the TRAFTAC system for generalizable transcription factor degradation.
 The ability to inhibit or modify enzyme function absent a catalytic pocket binding site target greatly expands the potentially druggable portion of the proteome. Furthermore, most classes of chimeric small molecules can act on many targets over their life cycle, lowering the effective dose compared to traditional inhibitors that act only on one protein at a time. These therapeutics provide an alternative mechanism of action that may be useful as a combination therapy in diseases where drug resistance is a concern. Chimeric drug activity is also highly dependent on distance between targeted proteins allowing effect to be effectively tuned through optimization of the linker structure.
 The existence of two or more binding domains increases the difficulty of synthesis for chimeric molecules. Each component must be discovered, optimized, and synthesized in such a way that they can be linked together, driving up cost relative to single-domain inhibitors. The large size of chimeric molecules (typically 700-1100 Da) makes effective delivery difficult and increases complexity in pharmacokinetic design. Care must be taken to ensure that the molecule is capable of passing through the cell membrane and subsisting long enough to have therapeutic effect. Additionally, protein-protein ternary complexes are generally unstable, adding to the difficulty of chimeric drug design