Development of Potent Selective and Dual CBP/p300 PROTAC Degraders
Creators: name: Thomas, Junius
Publisher: name: My University
Year: 2023
Subjects: subject: PROTACs
subject: Cancer research
subject: CBP/p300
subject: Medicinal Chemistry
subject: Chemical Biology
subject: Degraders
subject: Biological Chemistry
subject: Molecular, Cellular and Developmental Biology
subject: Oncology and Hematology
subject: Pharmacy and Pharmacology
subject: Chemistry
subject: Science (General)
subject: Health Sciences
subject: Science

description: Over the past two decades, CREB-binding protein (CBP) and E1A-associated protein p300 (p300) have become attractive therapeutic targets, as they serve as central nodes for diverse cellular signaling pathways that include proliferation and differentiation and have been implicated as oncogenes. When co-expressed in certain tumors, CBP/p300 regulate co-dependent signaling nodes in a coordinated manner, contributing to cancer cell proliferation. Extensive efforts in the development of ligands that target CBP/p300 have occurred over the past two decades. However, since CBP/p300 contain multiple domains and function as transcriptional coactivators, targeting of one domain may not be adequate to exert the desired pharmacologic effect. Therefore, I wanted to develop a novel class of CBP/p300 therapeutics. In this dissertation, I report the development of JET-209 as an exceptionally potent and efficacious small-molecule PROTAC degrader of both CBP and p300 proteins. Generally, having high affinity inhibitors with suitable selectivity is ideal for a successful PROTAC degrader development program. A class of CBP/p300 bromodomain inhibitors reported by Genentech attracted my attention and served as a starting point based on the status of their CBP/p300 bromodomain inhibitor program. I chose their bromodomain inhibitor GNE-207, as the ligand to develop a class of PROTAC degraders of CBP/p300. Even though GNE-207 was a weak inhibitor of cell proliferation in certain prostate and breast cancer models with IC50 values ranging from single digit to over 10 micromolar, I was able to develop a class of CBP/P300 PROTACs that inhibited the same cell lines with IC50 values as low as single digit nanomolar. During the SAR process, it was even discovered that some of the PROTACs displayed selectivity for CBP over p300 and vice versa. Employing the PROTAC technology, I successfully transformed a moderately potent CBP/p300 bromodomain inhibitor into exceptionally potent and selective CBP/p300 degraders. JET-209 exerted potent cell growth inhibition in a panel of leukemia cell lines. JET-209 effectively induced CBP/p300 degradation in human ALL and AML xenograft tissues and achieved tumor regression in an AML xenograft model and an ALL-xenograft model in mice at a tolerated dose-schedule. In chapter 1, the latest therapeutics targeting CBP/p300 are discussed, followed by a brief description of proteolysis targeting chimera (PROTAC) technology. Chapter 2 describes the design, synthesis, and SAR of the CBP/p300 PROTAC degraders. Chapter 3 provides insight into the therapeutic potential of JET-209 in acute leukemia and its mechanism of action, whereas chapter 4 discusses its utility in prostate cancer along with data pertaining to another extremely potent CBP/p300 PROTAC degrader, JET-105. Finally, Chapter 5 briefly discusses the discovery of selective CBP and selective p300 PROTAC degraders along with pharmacodynamic data using different xenograft models and provides a general discussion of the achievements described in this dissertation and potential future research directions based on lessons learned during this research. In conclusion, this dissertation provides insight into the development of potent selective and dual CBP/p300 PROTAC degraders. JET-209 serves as an excellent tool compound with which to answer important biological questions raised in the study of CBP/p300. The selective CBP and p300 PROTAC degraders also serve as vital chemical tools in investigating the pharmacological effect of selectively degrading one of these coactivator proteins. Thus, these chemical tools pave the way toward our goal of CBP/p300 targeted therapies for cancer.