Protein-protein interactions (PPIs) are central factors in all cellular signaling and gene regulation protein networks, and their misregulation has been associated with a variety of diseases, notably cancer. Inevitably, many PPIs are biologically compelling targets for drug discovery. However, PPIs feature large, flat binding surfaces, lacking the tight-binding cavities that define typical drug targets. Accordingly, many PPIs pose a fundamental thermodynamic challenge to the development of conventional small molecule modulators. A promising PPI inhibitor discovery strategy is to use miniature protein domain mimetics (PDMs) to reproduce the key interface contacts utilized by nature. PDMs are advantageous as medium-sized molecules with high surface complementarity and a broader set of contact points than typical small molecules, but are still limited because?by definition?only a portion of the total PPI binding energy is captured in the interaction. The binding affinity of the synthetic domains is often lower than the cognate full-length proteins. Targeted covalent inhibition is an orthogonal therapeutic approach traditionally employed to enhance binding affinities of small molecules, but the approach has a potential drawback as the high reactivity of typical covalent warheads may lead to nonspecific interactions and toxicity. Here we propose to develop computational methods for a new design strategy that will leverage the strengths of these two methods?PDMs and covalent inhibition? while simultaneously mitigating their respective limitations. The focus of the effort is to rationally discover potent inhibitors that will non-covalently recognize and then covalently target protein- protein binding interfaces with exquisite specificity.

Public Health Relevance

Protein-protein interactions (PPIs) are vital for numerous biological processes, from cellular signaling to gene regulation, and their misregulation has been associated with a variety of diseases, notably cancer. Inevitably many PPIs are biologically compelling targets for drug discovery. In this proposal, we aim to develop computational tools that results in highly specific and potent inhibitors of the Ras/Sos, ks-vFLIP/NEMO and MDM4/p53 interactions, as reagents for biological studies and leads for cancer drug development.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM120736-04
Application #
9747311
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Lyster, Peter
Project Start
2016-09-01
Project End
2020-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
New York University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
Rooklin, David; Modell, Ashley E; Li, Haotian et al. (2017) Targeting Unoccupied Surfaces on Protein-Protein Interfaces. J Am Chem Soc 139:15560-15563