Abstract NG06: Addressing scaffolding roles of oncogenic kinases with targeted protein degradation

Abstract

Abstract Proteolysis Targeting Chimera (PROTAC) technology has emerged over the last two decades as a powerful tool for targeted degradation of proteins. PROTACs are heterobifunctional small molecules which co-opt the ubiquitin proteasome system to destroy oncogenic proteins. The development of PROTACs for receptor tyrosine kinases (EGFR, Her2 and c-MET), a protein family previously thought to be intractable for induced protein degradation, will be described. The use of VHL-recruiting PROTACs against this protein family reveals several advantages of degradation over inhibition alone including more potent inhibition of cell proliferation, a more durable and sustained downstream signaling response. Combined, these findings demonstrate the ability to target receptor tyrosine kinases for degradation using the PROTAC technology and outline the advantages of this degradation-based approach. Application of the PROTAC technology to targets, including RTKs, in hematological malignancies has also provided potential therapeutic approaches and enhanced understanding of scaffolding roles of oncogenic kinases. The receptor tyrosine kinase FLT-3 is frequently mutated in acute myeloid leukemia; however, traditional small molecule inhibitors suffer from limited efficacy in the clinic. A FLT-3 targeting PROTAC with sub-nanomolar antiproliferative activity and the ability to induce tumor regression in vivo will be described. Additionally, the discovery of apoptosis suppression as a kinase independent activity of FLT-3 ITD will be described. While the use of kinase inhibitors of oncoprotein BCR-Abl have enabled durable responses in patients with chronic myeloid leukemia (CML), issues of drug resistance and residual leukemic stem cells remain. An allosteric BCR-Abl PROTAC demonstrates significant advantages compared to inhibition and identified scaffolding roles for BCR-Abl which are not addressed by inhibitors but can be abrogated by protein degradation. Concurrent treated with the allosteric PROTAC and orthosteric inhibitors proved synergistic, particularly against some clinically relevant BCR-Abl kinase domain mutants. Furthermore, investigation into the kinase independent roles of BCR-Abl in patient stem cells suggest that these persistent leukemic stem cells are BCR-Abl agnostic. Citation Format: George Burslem. Addressing scaffolding roles of oncogenic kinases with targeted protein degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr NG06.