[12] PROTACs are dimeric molecules that recruit specific intracellular proteins to the cellular quality control machinery (i.e., an E3 ubiquitin ligase) in a catalytic manner for subsequent removal by the proteasome.
[17] Prior to its work on PROTACs, the Crews lab's synthesis and mode of action studies of the natural product epoxomicin revealed that it is a potent and selective proteasome inhibitor.
[20][21] Crews’ initial research at Yale explored the synthesis and mode of action of the natural product epoxomicin, which revealed itself to be a potent and selective proteasome inhibitor via its epoxyketone pharmacophore.
[24] In 2003, Crews co-founded the biotechnology company Proteolix to develop YU101, which ultimately served as the parent compound of multiple myeloma drug carfilzomib (Kyprolis).
[29] Crews’ work in the field of induced proximity has led to the development of a number of investigational therapeutic candidates aimed at drugging proteins that are difficult to target using existing small molecule technology.
[32] PROTACs have the potential to allow pharmacological targeting of proteins previously thought "undruggable", such as those with inaccessible or non-selective active sites, including many responsible for drug resistance in cancer.
[16] Crews has founded three biotechnology companies to develop TACs discovered in his Yale research lab, each of which induces protein-protein interactions within distinct target classes to achieve a therapeutic effect.
[37][38] In 2019, Crews founded Halda Therapeutics, a venture-backed biotech company that is developing RIPTACs, or Regulated Induced Proximity Targeting Chimeras, for the treatment of cancer.