Craig Crews et al. presented the notion of PROTAC (Proteolysis Targeting Chimera: in 2001 to reduce protein levels instead of blocking protein function by exploiting the body's naturally occurring protein cleanup system to treat disease. PROTAC technology has become one of the hottest technologies in the field of novel drug development, favored by research institutes, pharmaceutical firms, and investment institutions after 20 years of constant improvement and development.

PROTAC is a heterobifunctional molecule with one end attached to a ligand that binds to the target protein and the other end connected to an E3 ligase ligand ( via a chemical linker. The PROTAC molecule forms a ternary complex with the protein of interest (POI) and E3 ligase, which ubiquitinates the target protein that is then identified and destroyed by the intracellular proteasome.

Traditional small molecules and antibodies inhibit the function of target proteins through an occupancy-driven mode of action, which requires high concentrations of inhibitors or monoclonal antibodies (mAbs) to occupy the active site of the target and block the transduction of downstream signaling pathways. In contrast, PROTAC is event-driven, not affecting the function of the protein, but mediating the degradation of the disease-causing target protein. Once PROTAC mediates the formation of the ternary complex and tags the target protein with ubiquitination, it is theoretically recyclable and therefore can be used repeatedly in catalytic amounts. Furthermore, PROTAC can cause the destruction of proteins that lack active sites, such as scaffold proteins, as long as they can provide binding effects, extending the range of targets significantly.

More than 100 proteins have been successfully degraded, according to statistics, including:
Kinases: RIPK2, BCR-ABL, EGFR, HER2, c-Met, TBK1, CDK2/4/6/9, ALK, Akt, CK2, ERK1/2, FLT3, PI3K, BTK, Fak, etc.
BET proteins: BRD2/4/6/9
Nuclear receptors: AR, ER, etc.
Other proteins: MetAp-2, Bcl-xL, Sirt2, HDAC6, Pirin, SMAD3, ARNT, PCAF/GCN5, Tau, FRS2, etc.

1. These include non-druggable targets such as the transcription factor regulatory protein pirin and the epigenetic-related protein PCAF/GCN5. In addition, according to a report released by Nature in March, at least 15 protein degraders (including PROTAC and molecular gels) will be in clinical trials by the end of 2021.

RAS (KRAS, HRAS and NRAS), the most commonly mutated genes in cancer, are important driver of lung, colorectal, and pancreatic cancers. In more than 40 years of discovery and research, there have been no drugs available for such targets.

Amgen's irreversible KRAS-G12C inhibitor AMG510 (Sotorasib) was approved in May, putting an end to the targets' non-druggability, yet degradation agents still have great potentials.

Crews et al. developed and synthesized PROTAC based on KRAS inhibitors AMG510 and MRTX849 for the KRAS-G12C mutation, and the activity assay identified degraders with satisfactory degradation activity, which could provide a novel way to tackle RAS.

2. Compared to traditional small molecule inhibitors, PROTAC can achieve selectivity at certain targets that is difficult to achieve with small molecules, and is also distinctive on elevating activity.

3. Small molecule inhibitors or antagonists are inevitably subject to acquired resistance during clinical use. Examples include EGFR-T790M and C797S resistance. Although resistance can be addressed by developing new generations of inhibitors, such as third- and fourth-generation EGFR, new resistance will emerge. PROTAC technology has shown some advantages in overcoming drug resistance.

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