Periodic Reporting for period 1 - Bump-BET (Bump and Hole approach to elucidate function of individual bromodomains of BET proteins)
Période du rapport: 2015-10-01 au 2017-09-30
At the same time, the researcher pursued a closely related project using a proteolysis targeting chimera (PROTAC) approach to target BET proteins. The researcher contributed to the report of the first-ever PROTAC-induced E3-target ternary complex and led an SAR study to understand E3 ligand selectivity in the context of ternary complex formation. These works provide structural basis for PROTAC-mediated target protein degradation.
In the PROTAC approach project, BET proteins are targeted by linking BET-inhibitor, JQ1, to E3 ligase VHL (Von Hippel–Lindau) ligand [2]. The researcher characterized and profiled the activity of these PROTAC molecules in cell and in vitro. The first PROTAC molecule reported by the host lab, MZ1, although based on a pan-selective BET-inhibitor scaffold, demonstrates a selective substrate degradation preference against BRD4 over BRD2 and BRD3. In a collaborative work within the Ciulli lab, first crystal structure of a PROTAC induced complex of E3-ligase with its target protein is reported [3]. A model explaining the observed selectivity is proposed and leads to the development structure-designed PROTAC, e.g. AT1, which shows exquisite selectivity for BRD4.
The researcher also leads a SAR study of another series of BET-targeting PROTAC molecules [4]. The researcher showed that by substituting the targeting recruitment warhead would result in a completely different selectivity profile against BET proteins. Extensive work on in vitro E3-PROTAC-BD complex formation was performed and the results were backed up by cellular protein degradation study.
Overview of the results
During the project period, an optimized bump-and-hole system on the BET BD has been established. It provides selective chemical tools for future cellular and in vivo target validation studies. The PROTAC approach demonstrates a strategy to achieve selective and efficient protein knock-down by small molecule. Structural basis for efficient PROTAC activity is established, supported by extensive SAR study both in vitro and in cell. This provides valuable knowledge for PROTAC design in the developing field.
The researcher’s work contributes to two peer-reviewed research papers on PROTAC [3,4] and one paper under revision on bump-and-hole . His contribution is also recognized by the field as he is invited as speaker at the 12th Annual Drug Discovery Chemistry Conference (2017) held in San Diego on Targeted Protein Degradation by Small Molecules. Knowledge gains in the project also enables him to co-author a review paper on the topic of chemical genetics in epigenetics [5].
1. Baud M.G.J. et al., Science 2014, 346(6209), 638-641.
2. Zengerle M. et al., ACS Chemical Biology 2015, 10(8):1770-7
3. Gadd M.S. et al. Nature Chemical Biology 2016, 13, 514–521.
4. Chan K.-H. et al. Journal of Medicinal Chemistry 2017, DOI: 10.1021/acs.jmedchem.6b01912
5. Runcie A. C. et al. Current Opinion in Chemical Biology 2016, 33, 186–194.
PROTAC is an approach very different from the conventional inhibition model. In theory, this can be applied to any target when a specific ligand is available, no matter where it binds on the target. This is a promising approach to targets previously regarded as non-druggable as an active site is not a pre-requisite. Work done by the researcher and his colleagues provides structural basis of PROTAC activity. This set an example for structure-based PROTAC development in the field. Work on PROTAC also starts to gain recognition in the board scientific community, for example the researcher was invited to the 12th Annual Drug Discovery Chemistry Conference (2017) and our work is recommended by F1000Prime [3].
1. French C.A. Adv. Cancer Res. 2016, 131, 21-58.
2. Andrieu G. et al., Drug Discov. Today Technol. 2016, 19, 45-50.
3. Murray B., 2017 Retrieved from https://f1000.com/prime/727397475