The design, synthesis and biological evaluation of PROTACs for CREBBP and p300

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This project deals with the design, synthesis and biological evaluation of proteolysis-targeting chimeras (PROTACs) for the histone acetyltransferases CREB binding protein (CREBBP) and the closely related p300. Both proteins are ubiquitously expressed and function as transcriptional coactivators that interact with a multitude of proteins. Thus, CREBBP and p300 are involved in essential biological processes such as proliferation, cell cycle, and cell differentiation. Many human cancer types are characterised by mutations in the CREBBP gene and arouse interest in CREBBP/p300 modulation as an important option in cancer pharmacotherapy. So far, there is no small molecule ligand, that is selective for CREBBP or p300 and would allow to investigate fundamental aspects of the biological function of CREBBP or p300, however.PROTACs are chimeric molecules that bind both the target protein and an E3 ligase. Consequently, the target protein will be ubiquitinated, recognised by the proteasome, and degraded. At the outset of the project, we will design and synthesise a PROTAC to degrade CREBBP and p300 and we will study its biological effects on a series of human cancer cell lines in vitro. Previous studies in the group of Prof. Conway identified a selective high affinity CREBBP/p300 bromodomain inhibitor, which is supposed to act as a binding motif for the protein of interest and forms the basis of the PROTAC design. As E3 ligase, we selected cereblon, von Hippel-Lindau (VHL), and MDM2 because ligands such as thalidomide, VH032, and nutlin have been established for them in the literature. The ligands for the protein of interest and the E3 ligase are connected by a linker, whose chain length will be investigated in the first step of structure-activity relationship to ensure optimised degradation of CREBBP and p300. Moreover, PROTACs shall be developed to selectively degrade either CREBBP or p300. To achieve this, we will optimise the linker in terms of chain length and attachment point of the CREBBP/p300 ligand, and choose different E3 ligase ligands. Finally, we will check the hypotheses that these selective PROTACs cause a different phenotype in cancer cell lines and that CREBBP and p300 are not redundant. The resulting PROTACs would provide tool compounds to obtain insights into CREBBP and/or p300 function, what has not been achieved by conventional small molecule inhibitors due to lack of selectivity. Furthermore, these compounds enable us to gain a deeper understanding of their involvement in the pathogenesis of numerous cancer types and offer access to the development of novel clinical candidates for cancer.