The receptor for the hepatocyte growth factor (HGF), a membrane-bound tyrosine kinase known as c- Met, has been linked to an assortment of cancers including lung, breast, colorectal and gastric. In the vast majority of tumors, analyses have shown that c-Met expression has become amplified to levels higher than in normal tissues such that downstream signaling pathways become overactivated and ligand-independent. c-Met signals through a variety of effectors, many of them associating with c-Met upon phosphorylation of several residues near the cytoplasmic tail. However, small molecule inhibitors of c-Met kinase activity have thus far performed disappointingly in clinical testing, with some trials having been terminated before they were completed. Consistent with this was the finding that elevated levels of c-Met in tumor samples are not accompanied by an elevated level of the kinase-active state of c-Met. The finding that other tyrosine kinases can activate downstream signaling of c-Met, nevertheless, demonstrate that c-Met can be an important node for oncogenic signaling. All these factors together suggest that the oncogenic potential of c-Met may be largely independent of its own kinase activity, and that downregulating c-Met rather than merely inhibiting its kinase activity may be the key to treating c-Met driven cancers. The Crews Lab has for many years been developing a class of small molecules that effectively cause the post-translational degradation of targeted proteins. These small molecules, known as PROTACs, facilitate the ubiquitination of the proteins they target, ultimately causing their degradation by the proteasome. This research plan proposes to design and synthesize one or more PROTACs that cause the degradation of c-Met by at least 90% and at low nanomolar potency in c-Met-driven cultured cancer cells. Upon reaching these criteria, the degraders will be evaluated using unbiased, high- throughput methods of RNA Seq. and SILAC to identify changes in the transcriptome and proteaome, respectively that are specific to c-Met degradation rather than c-Met inhibition. This way, the key downstream effectors for c-Met driven cancer aim to be determined. In parallel, the anti-cancer potential of c-Met-degrading PROTACs will be tested in mouse xenograft model using c-Met-driven cancer cells. The Crews Lab and the applicant have experience with all the experimental strategies in this research plan. If successful, the research conducted will result in the creation of a new chemical biology tool, the discovery of new biology associated with c-Met and the demonstration that a protein degradation approach to c-Met-driven cancers offers a viable therapeutic solution where currently none have been established.
Cancer remains a serious health problem in America, and the need remains for the creation of new medicines that more effectively fight the disease. Our goal in this proposal is to create a drug candidate that, rather than inactivate a diseased protein that drives cancer, will cause its complete and irreversible destruction. Such a drug would be more effective for longer periods and at lower concentrations, thereby potentially reducing side effects and making for a far superior anti-cancer therapeutic.
| Bondeson, Daniel P; Smith, Blake E; Burslem, George M et al. (2018) Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead. Cell Chem Biol 25:78-87.e5 |
| Burslem, George M; Smith, Blake E; Lai, Ashton C et al. (2018) The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study. Cell Chem Biol 25:67-77.e3 |
